WO2015000412A1 - Benzocyclobutene derivative and preparation method and pharmaceutical application thereof - Google Patents

Abstract

The present invention relates to a benzocyclobutene derivative and a preparation method and pharmaceutical application thereof. Specifically, the present invention relates to a compound expressed by formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, eutectic, or prodrug thereof, preparation methods thereof, a pharmaceutical composition thereof, and a pharmaceutical purpose of the compound or pharmaceutical composition of the present invention, especially a purpose of functioning as a GPR40 receptor (G-protein coupled receptor) agonist. Definitions of substituent groups in formula (I) are the same as those in the specification.

Description

 Benzocyclobutene derivative, preparation method thereof and application thereof in medicine

 The present invention relates to a benzocyclobutene derivative, a preparation method thereof and its use in medicine, in particular to a novel benzo compound having a G protein-coupled receptor 40 (GPR40) receptor function regulating function. A furan derivative or a stereoisomer thereof, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic or a prodrug, a process for the preparation thereof, a pharmaceutical composition comprising the same, and its use in medicine. Background technique

 Diabetes and its complications seriously affect people's quality of life and become one of the important causes of death. Excessive blood sugar levels in diabetes lead to typical symptoms of polyuria, polydipsia and polyphagia. Diabetes complications such as Kidney damage, diabetic ketoacidosis and heart disease can be life threatening. Type II diabetes is the most common type of diabetes, mainly in adulthood, mainly due to insufficient insulin secretion or insulin resistance (ie, the body tissue can not effectively respond to endogenous insulin), genetic and environmental factors can be Causes insulin resistance.

 If diabetics cannot effectively control their blood sugar through diet and exercise, they need to take hormonal drugs or oral hypoglycemic agents. Oral hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolidinediones (TZDs), a-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP- IV), sodium-glucose cotransporter 2 (SGLT-2) inhibitors and other drugs. However, these hypoglycemic agents have side effects such as hypoglycemia, weight gain, cardiovascular risk, and genitourinary tract infections (Vinod S. Deshmukh et al. (2013). International Journal of Basic & Clinical Pharmacology, 2, 4-11 These side effects further increase the burden on diabetic patients. Therefore, it is necessary to develop a new generation of hypoglycemic agents with a novel mechanism of action.

G-protein coupled receptor 40 (GPR40) is a novel target with hypoglycemic potential and is highly expressed in islet beta cells. GPR40, also known as fatty acid receptor 1 (FFAR1), is a membrane receptor belonging to the homologous G protein-coupled receptor superfamily and is highly conserved among many species. G protein-coupled receptors have seven transmembrane structures that can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses. GPR40 can be activated by medium-long-chain free fatty acid CFFAs (Itoh Y et al. (2003) ). Nature, 422, 173-176). In addition to being an energy source, FFAs are also an important signaling molecule that promotes insulin secretion, a function that is primarily achieved through GPR40. The interaction of FFAs with GPR40 increases Ca ²⁺ flux through PLC or L-type Ca ²⁺ channel signaling pathways in islet beta cells, which in turn leads to cellular responses (Fujiwara et al. (2005). Am J Physiol Endocrinol Metab, 289, E670 -E677). Studies have shown that in animal models, agonistic GPR40 is effective in lowering blood glucose; in clinical trials, short-term and long-term treatment with GPR40 agonists promotes glucose-induced insulin secretion and increases glucose tolerance (K Nagasumi et al. (2009) .Diabetes, 58, 1067-1076), and since GPR40 promotes insulin secretion only at high levels of blood glucose, the risk of hypoglycemia is low. Fasiglifam hemihydrates (TAK-875) is a GPR40 agonist that has now entered Phase III clinical and proven effective. Studies have shown that: in the animal model of diabetes, fasiglifam hemihydrate CTAK-875) promotes insulin secretion and can effectively control blood glucose, but does not promote insulin secretion in normal rats (Tsujihata Y et al. (2010). Diabetes, 59, A165 In clinical trials, fasiglifam hemihydrates (TAK-875) also showed significant hypoglycemic effects with a lower risk of hypoglycemia (T. Araki et al. (2012). Diabetes, Obesity and Metabolisml 4, 271-278) . Other GPR40 agonists have also been developed, such as JTT-851, LY-2881835 and the like.

 In summary, GPR40 is a safe and feasible new target for oral hypoglycemic agents. The development of GPR40 agonists has very important research value and application prospects. A number of research literatures related to GPR40 agonists are currently published.

US2006258722 describes GPR40 receptor modulators which are useful as insulin secretion promoters and preventive and/or therapeutic agents for diabetes, under the structural formula:

Wherein, the cyclic group of the optionally substituted substituent of Ar, the cyclic group of the optional substituent of A, and not substituted by thiazole, oxazole, imidazole and pyrazole, each independently selected from a bond or containing 1 a chain of -5 atoms, Xc is selected from 0, S, SO or S0 ₂ , Xd is selected from a bond, CH or CH ₂ , D is selected from a benzene ring, a thiophene or a thiazole, and B is selected from a ring of 5 to 7 members, R ^{1 is} selected from a hydroxyl group. The specific description in this patent is not considered to be part of the present invention.

CN101616913 describes a fused ring compound which can function as an insulin secretion promoting agent and a GPR40 receptor function regulating effect of diabetes prevention and/or therapeutic drugs, and has the following structural formula:

Wherein R ^{1 is} selected from -S0 ₂ -R ⁶ , R ^{6 is} selected from d- ₆ fluorenyl or optionally substituted 1,1-dioxotetrahydrothiopyranyl, and X is selected from a bond or a divalent hydrocarbon group; R ² and R ^{3 are} selected from H, a halogen atom, a substituted hydrocarbon group or a substituted hydroxyl group; R ⁴ and R ^{5 are} selected from d- ₆ fluorenyl substituted by a hydroxy group; A is selected from a benzene ring, and B is selected from 5 to A 7-membered ring, Y is selected from a bond or CH ₂ , and R is selected from a hydroxyl group. The specific description in this patent is not considered to be part of the present invention.

 US7786165 describes the structure of GPR40 as follows:

Wherein, Ar is optionally a cyclic group of a substituent, and is not substituted by a 4-piperidinyl group, B is optionally a ring of a substituent, and is not substituted by a thiazole or an oxazole, and V is selected from a bond or contains 1-3 a chain of atoms, and this chain is not a -N=N- group, and W is selected from a bond or d- ₆垸 a group, X, Xa is selected from CH or N, Y is selected from O or CR ⁶ R ⁷ , and R ¹ and R ^{la are} selected from H, halogen, d- ₆ fluorenyl or d- ₆ methoxy, and R ^{2 is} selected from H a d- ₆ fluorenyl or an optionally substituted acyl group, R ³ and R ^{4 are} selected from H or halogen, and R ^{5 is} selected from a substituted hydroxy group or a substituted amine group, and the compound specifically described in US7786165 is not considered to be part of the present invention. .

 WO2010143733 describes a GPR40 receptor modulator which can be used as an insulin secretion promoting agent and a preventive and/or therapeutic drug for diabetes, and has the following structural formula:

Wherein R ^{1 is} selected from halogen, hydroxy, optionally substituted d- ₆ fluorenyl or optionally substituted d- ₆ fluorenyloxy; R ^{2 is} selected from substituted hydroxy, R ^{3 is} selected from H, halogen or optionally substituted D- ₆ fluorenyl, X is CH ₂ , Y is selected from CH ₂ , NH or 0, Z is selected from CH or N, and A is selected from halogen, optionally substituted amine or 4-13 membered ring. Compounds specifically described in WO2010143733 are not considered to be part of the present invention. Summary of the invention

 The present invention relates to a compound of the formula or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,

 among them:

R is selected from H or d- ₈ fluorenyl;

Ring A is selected from a 5- to 8-membered carbocyclic group or a 5- to 8-membered heterocyclic group, and said heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or 3 (=0) ₁₁ . The carbocyclic or heterocyclic group may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, nitro, cyano, d- ₈ fluorenyl, d- ₈ methoxy, C _{2 -8} alkenyl, C _{2 -8} alkynyl, -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C Substituting (=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ or -(CH ₂ ) _m -NR ⁷ R ^7a ; wherein when having a plurality of substituents The substituents may be the same or different, and the similar descriptions below have the same meanings and will not be described again;

Ring B, including atoms attached to the benzene ring, together form a four-membered ring, and ring B may optionally be further from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, nitro, cyano, d - ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m -C (=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ or -(CH ₂ ) _m -NR ⁷ R ^7a Substituted by R ¹ and R ⁴ are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- ₈ fluorenyl or d- ₈ decyloxy, said amino, fluorenyl or embankment group optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, cyano, Ci_ ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl Base, -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH _{2 m} -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a or -(CH ₂ ) _m -C(=0)-NR ⁷ substituted by a substituent of R ^7a ; R ² And R ³ are each independently selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- ₈ decyl or d- ₈ decyloxy, said amino, fluorenyl or decyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, hydroxy, cyano, Ci- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m Substituting a substituent of -S(=0)nR ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a or -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a ;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, hydroxy, nitro, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -( CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-R ⁷ , 3 to 10 membered carbocyclic group, 4 to 10 membered heterocyclic group, 3 to 10 membered carbon Cycloalkyloxy or 4 to 10 membered heterocyclyloxy, said fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further substituted with 0 to 4 substituents selected from F, Cl, Br, I, = 0, hydroxy, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ Alkynyl, -(CH ₂ ) _m -C(=0)-R\ -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH _{2 m} -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )- ^{C (= 0) -NR 7 R} 7a, -N (R 7b) -C (= 0) -R 7, 3 to 10 membered carbocyclic ring, 4 to 10-membered heterocyclic group, C 3-10 yuan A substituted oxy group or a 4-10 yuan heterocyclic oxy group substituted with the group, and the heterocyclic group containing 1 to 4 heteroatoms selected from N, 0 or 3 (= (¾ of _an atom or group; wherein When having a plurality of heteroatoms, the heteroatoms may be the same or different, and the similar descriptions below have the same meanings and will not be described again;

Alternatively, R ⁵ and R ⁶ may form a 4 to 8 membered carbocyclic ring or a 5 to 8 membered heterocyclic ring, and the carbocyclic or heterocyclic ring may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, and I. , = 0, hydroxy, nitro, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0 )-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ or Substituted by a substituent of -(CH ₂ ) _m -NR ⁷ R ^7a , and the heterocyclic ring contains 1 to 4 atoms or groups selected from N, 0 or S(=0) _n ;

Y is selected from the group consisting of a single bond, -0-, -NR ⁷ -, -S(=0) _n -, -C(=0)-, -d_ ₈ fluorenylene or -O-Cu fluorenylene, said The fluorenylene group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , cyano, hydroxy, d- ₈ fluorenyl, Ci- ₈ fluorenyloxy , C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m -C (= 0) -0-R 7, - (CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -0-C(=0)-0-R ⁷ or -NR Substituted by a substituent of ⁷ R ^7a ;

X is selected from H, F, Cl, Br, I, hydroxy, nitro, cyano, alkyl with ₈ D-, D- ₈ embankment group, C ₂ - ₈ alkenyl group, _ ₈ alkynyl group, - (CH _{2 m} -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(= 0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)- NR ⁷ R ^7a , -N(R ^7b )-C(=0)-R ⁷ , -(CH ₂ ) _n -3 to 10 membered carbocyclic group, -(CH ₂ ) _n -4 to 10 membered heterocyclic group, -(CH ₂ ) _n -0-3 to 10 membered carbocyclic group or 4 to 10 membered heterocyclic oxy group, said fluorenyl group, hydrazine Further, the alkenyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl or heterocyclyloxy group is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, nitro, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m - C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0)nR ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -( CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-R ⁷ , Substituted with a 3- to 10-membered carbocyclic group, a 4 to 10 membered heterocyclic group, a 3 to 10 membered carbocyclic oxy group or a 4 to 10 membered heterocyclic oxy group, and the heterocyclic group contains 1 Up to 4 atoms or groups selected from N, 0 or 3 (=0) ₁₁ ;

R ⁷ , 1 and R ^7b are each independently selected from the group consisting of H, hydroxy, amino, carboxy, d- ₈ fluorenyl, d- ₈ methoxy, C _{2 -8} alkenyl,

C _{2 .8} alkynyl, 3 to 10 membered carbocyclic group, 4 to 10 membered heterocyclic group, 3 to 10 membered carbocyclyloxy group or 4 to 10 membered heterocyclic oxy group, said amino group, fluorenyl group , methoxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further selected from 0 to 4 selected from F, Cl, Br, I, =0 , hydroxy, amino, nitro, cyano, carboxy, d- ₈ alkyl with, d_ ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl group, 3-10 yuan carbocyclyl, 4-10 Substituted by a heterocyclic group, a 3- to 10-membered carbocyclyloxy group or a 4- to 10-membered heterocyclic oxy group, and the heterocyclic group contains 1 to 4 selected from N, 0 or S ( =0) an atom or group of _n ;

 p is selected from 0, 1, 2 or 3;

 q is selected from 0, 1, 2, 3 or 4;

t is selected from 0, 1 or 2 (when t is 0, it means that -COOR is directly attached to ring A; when t is 2, there are two identical or different R ² and two identical or different in the compound R ³ ) ;

 m is selected from 0, 1, 2, 3, 4 or 5;

 n is selected from 0, 1 or 2.

 In the present invention, the phrase "as a selection" means that the scheme after "as a selection" is a side-by-side selection relationship with the scheme before "as a selection", rather than a further selection in the foregoing scheme.

 In a preferred embodiment of the invention, the compound or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the formula (II) ) the compound shown:

 among them:

R is selected from H or d- ₄ fluorenyl, preferably H or d- ₂ fluorenyl, more preferably H;

V) Χ°>") N rS ^ Y , ^S ring A is selected from , ^, \ , \ , , , or ' U, preferred Hey. , 丫. \

Or, more preferably, and ring A may be further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, =0, amino, hydroxy, d- _4- indenyl or _-4- indolyloxy Replace

 Ring B, comprising an atom attached to the benzene ring to form a four-membered ring, and ring B may optionally further be from 0 to 4 selected from F,

Cl, Br, I, = 0 , hydroxy, nitro, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, - (CH _{2) m} -C(=0)-R -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n - Substituted by a substituent of R ⁷ or -(CH ₂ ) _m -NR ⁷ R ^7a ;

R ¹ and R ⁴ are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- _4- indenyl or _-4- decyloxy, preferably F, C1 or d- ₄垸Further, the amino group, thiol group or decyloxy group is further optionally selected from 0 to 3

Substituted by a substituent of F, Cl, Br, I or a hydroxyl group;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- _4- indenyl or d- ₄ decyloxy, preferably H, F, Cl , Br, I, hydroxy or _-4 fluorenyl, more preferably H, F, Cl, hydroxy or d ₄ fluorenyl, further preferably H, C1 or d- ₄ fluorenyl, said fluorenyl or decyloxy optionally Further 0 to 3 selected from F,

Substituted by a substituent of Cl, Br, I, hydroxy, d-4 fluorenyl or 1,4-oxooxy;

Y is selected from a single bond, -0-, -NR ⁷ -, -S(=0) _n -, -C(=0)-, -d_ ₄ fluorenylene or -O-CM fluorenylene, preferably a single bond ,

-0-, _-N R ⁷ -, -d_ ₄ fluorenylene or -O-CM fluorenylene, more preferably a single bond, -0- or -NR ⁷ -, further preferably -0-, said Aa The base is further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , cyano, hydroxy,

4-mercapto, d-4 methoxy, C ₂ -4 alkenyl, C ₂ -4 alkynyl, -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C( =0)-0-R ⁷ ,

-(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -0-C(=0)-0-R ⁷ or - Substituted by a substituent of NR ⁷ R ^7a ;

X is selected from H, F, d ₄ fluorenyl, d ₄ methoxy, C _{2 -8} alkenyl, C _{2 -8} alkynyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , - (CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group, -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group or 4 to 8 membered Heterocyclic oxy group, preferably H, d ₄ fluorenyl, d ₄ methoxy, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic ring a group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group, -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group or 4 to 8 membered heterocyclic oxy group, more preferably H, d- ₄ fluorenyl, d- ₄ methoxy, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n - a 4- to 8-membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8-membered carbocyclic group, further preferably H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH _{2 n} - 3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, said fluorenyl group, hydrazine An oxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl or heterocyclyloxy group is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d_ ₄ alkyl with, d_ ₄ embankment Group, C ₂ _ ₈ alkenyl, C ₂ _ ₈ alkynyl _{group, - (CH 2) m -S} (= 0) n -R 7, 3 to. 8 membered carbocyclic ring, 4 to 8-membered heterocyclic group, 3 Substituted to a 8-membered carbocyclyloxy group or a 4- to 8-membered heterocyclic oxy group, and the heterocyclic group contains 1 to 4 atoms selected from N, 0 or 3 (=0) ₁₁ Or group;

R ⁷ and R ^7a are each independently selected from H, hydroxy, amino, carboxy, d- ₄ alkyl with, d- ₄ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, carbocycle 3-8 yuan a 4- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 4- to 8-membered heterocyclic oxy group, preferably H, hydroxy, amino, d- _4- indenyl or _-4- decyloxy, further Preference is given to hydroxy or d- _4- indenyl, said amino, indolyl, decyloxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclooxy optionally further 0 to 4 choices g F, Cl, Br, I , hydroxy, amino, nitro, cyano, carboxy, d- ₄ alkyl with, d- ₄ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl group, 3 to Substituted with an 8-membered carbocyclic group, a 4 to 8 membered heterocyclic group, a 3 to 8 membered carbocyclyloxy group or a 4 to 8 membered heterocyclic oxy group, and the heterocyclic group contains 1 to 4 An atom or group selected from N, 0 or 3 (=0) ₁₁ ;

 p is selected from 0, 1 or 2;

 q is selected from 0, 1 or 2;

 m is selected from 0, 1, 2, 3, 4 or 5;

 n is selected from 0, 1 or 2.

 In a preferred embodiment of the invention, the compound or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the formula (II) ) the compound shown:

 among them-

优选 ¥

且环 A可以进一步被 0至 3个任选自 F、 Cl、 Br、 I、 =0、 氨 基、 羟基、 d— ₄垸基或者^— ₄垸氧基的取代基所取代； R selection

Preferred ¥

And Ring A may be further substituted with 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, =0, amino, hydroxy, d- ₄ fluorenyl or _-4- yloxy;

Ring B, including atoms attached to the benzene ring, together form a four-membered ring, and Ring B may optionally be further from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, amino, nitro, cyano Substituted by a substituent of a carboxyl group, a d- ₄ fluorenyl group or a _4- decyloxy group;

R ¹ and R ⁴ are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- _4- indenyl or _-4- methoxy, preferably F, C1 or methyl. Said amino, thiol or decyloxy group is optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I or hydroxy;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- _4- indenyl or CM methoxy, preferably H, F, Cl, Br Or I or d- ₄ fluorenyl, more preferably H, F, CI or d- ₄ fluorenyl, further preferably H or d-4 fluorenyl, said amino, fluorenyl or decyloxy optionally further being 0 to Substituting three substituents selected from the group consisting of F, Cl, Br, I, hydroxy, d- ₄ fluorenyl or _-4- methoxy;

Y is selected from a single bond, -0-, -NR ⁷ -, -S(=0) _n -, -C(=0)-, -d_ ₄ fluorenylene or -O-CM fluorenylene, preferably a single bond , -0- or -NR ⁷ -, more preferably -0-, the fluorenylene group optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , CF ₃ , cyano, hydroxy, d - 4 fluorenyl, d - 4 decyloxy, C ₂ - 4 alkenyl, C ₂ - 4 alkynyl, -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-0-R ⁷ , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -0-C(=0)-0-R ⁷ or -NR ⁷ R ^7a Substituted by a substituent;

X is selected from H, F, d- 4 alkyl with, d- 4 embankment group, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -S} (= 0) n -R 7 , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group, -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group or 4 to 8-membered heterocyclic oxy group, preferably H, d ₄ fluorenyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -( CH ₂ ) _n -4 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, more preferably H, -(CH ₂ ) ₃ -S(=0)2-R ⁷ -(CH ₂ ) _n -4 to 6 membered carbocyclic group, -(CH ₂ ) _n -5 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 5 membered carbocyclic group, Further, the fluorenyl, decyloxy, alkenyl, alkynyl, carbocyclic, heterocyclic or heterocyclic oxy group is further further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, and nitro , cyano, carboxy, d ₄ fluorenyl, d ₄ methoxy, C _{2 -8} alkenyl, C _{2 -8} alkynyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , 3 Substituted to a substituent of an 8-membered carbocyclic group, a 4 to 8 membered heterocyclic group, a 3 to 8 membered carbocyclic oxy group or a 4 to 8 membered heterocyclic oxy group, preferably 0 to 4 selected from F, Cl, Unsubstituted or d- ₄ embankment group substituted group, more preferably 0-2 groups selected from hydroxy or methoxy substituent, and said heterocyclic group containing 1 to 4 heteroatoms selected from N, 0 or 3 (=0) ₁₁ atoms or groups;

R ⁷ and R ^7a are each independently selected from H, hydroxy, amino, carboxy, d- ₄ alkyl with, d- ₄ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, carbocycle 3-8 yuan a 4- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 4- to 8-membered heterocyclic oxy group, preferably H, hydroxy, amino, d- _4- indenyl or _-4- decyloxy, further Preference is given to hydroxy or d- _4- indenyl, said amino, indolyl, decyloxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclooxy optionally further is selected from 0-4 g F, Cl, Br, I , hydroxy, amino, nitro, cyano, carboxy, d- ₄ alkyl with, d- ₄ embankment group, C ₂ - ₈ alkenyl group, an alkynyl group _ ₈ Substituted with a 3- to 8-membered carbocyclic group, a 4- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclyloxy group or a 4- to 8-membered heterocyclic oxy group, and the heterocyclic group is contained 1 to 4 atoms or groups selected from N, 0 or 3 (=0) ₁₁ ;

 p is selected from 0, 1 or 2;

 q is selected from 0, 1 or 2;

 m is selected from 0, 1, 2, 3, 4 or 5;

 n is selected from 0, 1 or 2.

 A preferred embodiment of the invention, a compound of the formula (II) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,

 among them:

R is selected from H _; ring

 Ring B, including atoms attached to the benzene ring, together form a four-membered ring, and Ring B may optionally be further from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, d-4 fluorenyl or ^-4 Substituted by a substituent of an oxy group;

R ¹ and R ⁴ are each independently selected from the group consisting of F, Cl, Br, I, hydroxy or _-4 -yl, preferably F, CI or methyl;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- _4- indenyl or CM methoxy, preferably H, F, Cl, Br , I or d- ₄ thiol, more preferably H, F, CI or C _M thiol, further Preferably H or d- ₄ fluorenyl;

Y is selected from a single bond, -0-, -NR ⁷ -, -d_ ₄ fluorenylene or -O-CM fluorenylene, preferably a single bond, -0- or -NR ⁷ -, more preferably -0- The fluorenylene group is optionally further substituted with 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, CM thiol or _-4- decyloxy. Replaced

X is selected from H, d ₄ fluorenyl, d ₄ methoxy, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclyl, -( CH ₂ ) _n -4 to 8 membered heterocyclic group, -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group or 4 to 8 membered heterocyclic oxy group, preferably H, d- ₄ fluorenyl, - (CH ₂ ) _m -S(=0) _n -R\ -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group or, more preferably, H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ , -(CH ₂ ) _n -4 to 6 membered carbocyclic group, - (CH ₂ ) _n -5 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 5 membered carbocyclic group, said fluorenyl group, decyloxy group, carbocyclic group, heterocyclic group or hetero The cyclooxy group is further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- _4- indolyl, d- _4- decyloxy, -(CH ₂ ) _m -S(=0) _n -R\ 3 to 8 membered carbocyclic group, 4 to 8 membered heterocyclic group, 3 to 8 membered carbocyclic oxy group or 4 to 8 membered heterocyclic oxy group group substituted by, preferably 0-4 selected from F, Cl, hydroxy or ^ - embankment group substituted ₄ substituents, more preferably 0-2 groups selected from hydroxy or methoxy Substituted with a substituent, and the heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or 3 (=0;) ₁₁ ;

R ⁷ is selected from H, hydroxyl, amino, carboxyl, d- ₄ alkyl with, d- ₄ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl group, 3-8 yuan carbocyclyl or 4-8 a heterocyclic group, preferably H, amino, d- ₄ fluorenyl or _-4- decyloxy, more preferably d- ₄ fluorenyl, and the heterocyclic group contains 1 to 4 selected from N, 0 or S Hetero atom

 p is selected from 0 or 1 ;

 q is selected from 0 or 1 ;

 m is selected from 0, 1, 2, 3, 4 or 5, preferably 3 or 4, more preferably 3;

 n is selected from 0, 1 or 2.

 Preferred embodiments of the invention, the compound or a compound thereof: a stereoisomer, a hydrate, an ester, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic III):

 Wherein - ring B, including the atom attached to the phenyl ring, together form a four-membered ring, and ring B may be optionally further substituted with from 0 to 4 substituents selected from F or C1;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br, I, hydroxy or d- ₄ fluorenyl, preferably H, F, CI or d- ₄ fluorenyl, more preferably H, C1 or d- ₄垸Further, preferably H or d- ₂ fluorenyl;

Y is selected from a single bond, -0 or -NR ⁷ -, preferably -0-; X is selected from H, d ₄ fluorenyl, d ₄ methoxy, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclyl, -( CH ₂ ) _n -4 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, preferably H, d ₄ fluorenyl, -(CH ₂ ) _m -S (=0) _n- R ⁷ (CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, More preferably, H, -(CH ₂ ) _m -S(=0) _n -R ⁷ (CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, the fluorenyl, decyloxy, carbocyclic or heterocyclic group optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, Substituted with a substituent of I, hydroxy, CM thiol, d- ₄ methoxy, 3 to 8 membered carbocyclyl or 4 to 8 membered heterocyclyl, preferably 0 to 4 selected from hydroxy or methoxy Substituted with a substituent, and the heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or S(=0) _n ;

R ^{7 is} selected from H, hydroxy, amino, d- ₄ fluorenyl or d- ₄ decyloxy, preferably d- ₄ fluorenyl, further preferably d- ₂ fluorenyl; m is selected from 0, 1, 2, 3 or 4 , preferably 3 or 4, more preferably 3;

 n is selected from 0, 1 or 2.

 Preferred embodiments of the invention, the compounds or compounds represented by stereoisomers, hydrates, esters, metabolites, solvates, pharmaceutically acceptable salts thereof, eutectic IV):

 among them-

R ⁵ and R ⁶ are each independently selected from H, F, Cl, hydroxy or d ₄ fluorenyl, preferably H, C 1 or d ₄ fluorenyl, more preferably H or d ₂ fluorenyl;

X is selected from H, d ₄ fluorenyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To an 8-membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, preferably H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ , -(CH ₂ ) _n -4 to 6 membered carbocyclic group, -(CH ₂ ) _n -5 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 5 membered carbocyclic group, said fluorenyl group, carbocyclic group Or the heterocyclic group is optionally further substituted by 0 to 4 substituents selected from F, Cl, hydroxy, d- ₄ fluorenyl or 4 to 8 membered heterocyclic group, preferably 0 to 4 selected from F, C1 Substituted with a substituent of a hydroxyl group or a methoxy group, and the heterocyclic group contains 1 to 2 atoms or groups selected from N, 0 or S(=0) _n ;

R ^{7 is} selected from a hydroxyl group or a CM fluorenyl group, preferably a d- ₄ fluorenyl group, more preferably a d- ₂ fluorenyl group;

 m is selected from 2, 3 or 4, preferably 3 or 4, more preferably 3;

 n is selected from 0, 1 or 2.

 A preferred embodiment of the invention, a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R ⁵ and R ⁶ are each independently selected from H or d- ₄ fluorenyl, preferably H or d- ₂ fluorenyl;

X is selected from H, d ₂ fluorenyl, -(CH ₂ ) ₃ -S(=0)2-R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To 8 yuan heterocycle Or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, preferably H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ , -(CH ₂ ) _n -4 to 6 Carbocyclyl, -(CH ₂ ) _n -5 to 8-membered heterocyclic or -(CH ₂ ) _n -0-3 to 5-membered carbocyclic group, said fluorenyl or heterocyclic group optionally further Substituted to two substituents selected from a hydroxyl group, a d- _4- methoxy group or a 4- to 6-membered heterocyclic group, preferably substituted with 0 to 2 substituents selected from a hydroxyl group or a methoxy group, and The heterocyclic group contains 1 to 2 atoms or groups selected from N, 0 or 3 (= (3⁄4 ₁ ;

R ^{7 is} selected from the group consisting of d- ₄ fluorenyl, preferably d- ₂ fluorenyl;

 n is selected from 0, 1 or 2.

 A preferred embodiment of the invention, a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R ⁵ and R ⁶ are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H, methyl or ethyl;

, cb或者 fl 优选 H、 -(CH₂)₃-S(=0)2-R⁷、

, cb or fl is preferably H, -(CH ₂ ) ₃ -S(=0)2-R ⁷ ,

R ^{7 is} selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl.

 A preferred embodiment of the invention, a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R ⁵ and R ⁶ are each independently selected from H, methyl or ethyl, eumethyl;

X is selected from H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ ,

R ^{7 is} selected from methyl or ethyl, preferably methyl.

 A preferred embodiment of the invention, a compound of the formula (I) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected From the compound of the formula (II):

among them- R is selected from H or d- ₄ fluorenyl, preferably H;

 Hey.

 Ring A is

 Ring B, comprising atoms connected to the benzene ring to form a four-membered ring;

R ¹ and R ⁴ are each independently selected from F, Cl, Br or d-4, preferably F, CI or methyl;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br or d-4, preferably H or methyl;

Y is selected from a single bond, -0- or -O-CM fluorenylene, preferably -0-, and the fluorenylene group is further further selected from 0 to 4 selected from -(CH ₂ ) _m -S (=0 Substituted by a substituent of _n -R ⁷ ;

X is selected from H, d ₄ fluorenyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To an 8-membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, preferably H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 to 8 membered heterocyclic group or -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, more preferably H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -4 to 6 membered carbocyclic group, -(CH ₂ ) _n -5 to 8 membered heterocyclic group or -(CH ₂ ) _n -0 a 3- to 5-membered carbocyclic group, which is optionally further substituted with 0 to 4 substituents selected from a hydroxyl group or a d- ₄ alkoxy group, and The heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or 3 (=0) ₁₁ ;

R ^{7 is} selected from H or d- ₄ fluorenyl, preferably H or d- ₂ fluorenyl, more preferably methyl;

 p is selected from 0, 1 or 2;

 q is selected from 0, 1 or 2;

 m is selected from 0, 1, 2, 3, 4 or 5;

 n is selected from 0, 1 or 2.

 Preferred embodiments of the invention, the compound of the formula (II) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein The compound is selected from the compounds of the formula (III):

 among them:

 Ring B, comprising atoms connected to the benzene ring to form a four-membered ring;

R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br or d- ₄ , preferably! ! Or ^ - ₂ fluorenyl, more preferably H or methyl;

 Y is selected from -0- or -O-CM fluorenylene, preferably -0-;

X is selected from H, d ₄ fluorenyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To an 8-membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, preferably H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To an 8-membered heterocyclic group or a -(CH ₂ ) _N -0-3 to 8 membered carbocyclic group, more preferably H, -(CH ₂ ) _M -S(=0) _N -R ⁷ , -(CH ₂ ) _N -4 to 6 membered carbocyclic group, -(CH ₂ ) _N -5 to 8 membered heterocyclic group or -(CH ₂ ) _N -0-3 to 5 membered carbocyclic group, said fluorenyl group, carbocyclic group Or a heterocyclic group is optionally further substituted with from 0 to 4 substituents selected from hydroxy or CM methoxy;

R ^{7 is} selected from H or d- ₄ fluorenyl;

 m is selected from 0, 1, 2, 3 or 4;

 n is selected from 0, 1 or 2.

 A preferred embodiment of the invention, a compound of the formula (III) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of Compounds of formula 0V):

 among them:

R ^{5 is} selected from H or d- ₄ fluorenyl, preferably H or d- ₂ fluorenyl, more preferably H or methyl;

R ⁶ is H;

X is selected from H, -(CH ₂ ) _M -S(=0) _N -R ⁷ , -(CH ₂ ) _N -4 to 6-membered carbocyclic group, -(CH ₂ ) _N -5 to 8 membered heterocyclic ring Base or

a -(CH ₂ ) _N -0-3 to 5-membered carbocyclic group, which is optionally further substituted with 0 to 2 substituents selected from a hydroxyl group or a d- ₄ alkoxy group ;

R ^{7 is} selected from the group consisting of CM thiol, preferably d- ₂ fluorenyl, more preferably methyl;

 m is selected from 2, 3 or 4, preferably 3;

 n is selected from 0, 1 or 2.

 A preferred embodiment of the invention, a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R ^{5 is} selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H or methyl;

R ⁶ is H;

, 优选 H、 -(CH₂)₃-S(=0)2-R⁷、 i、 C^^Q 或者 XH, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ ,

, preferably H, -(CH ₂ ) ₃ -S(=0)2-R ⁷ , i, C^ ^Q or

R ^{7 is} selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl- A preferred embodiment of the invention, a compound of the formula ν) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R ^{5 is} selected from H, methyl or ethyl, preferably methyl;

R ⁶ is H;

i、 X - ^⁷或者 — ίX is selected from H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ ,

i, X - ^ ⁷ or - ί

R ⁷ is a methyl group.

 Preferred embodiments of the invention, the compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected From the compound of the formula (V):

 among them:

R ^{4 is} selected from H, F, CI or methyl;

R ^{5 is} selected from H or d- ₄ fluorenyl, preferably H or d- ₂ fluorenyl, more preferably H or methyl;

X is selected from H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -4 to 6-membered carbocyclic group, -(CH ₂ ) _n -5 to 8 membered heterocyclic ring Or a -(CH ₂ ) _n -0-3 to 5-membered carbocyclic group, the carbocyclic or heterocyclic group optionally further having 0 to 2 substituents selected from a hydroxyl group or a d- ₄ alkoxy group Replaced

R ^{7 is} selected from H or d- ₄ fluorenyl, preferably H or d- ₂ fluorenyl, more preferably methyl;

 m is selected from 0, 1, 2, 3 or 4, preferably 3;

 n is selected from 0, 1 or 2.

 A preferred embodiment of the invention, a compound of the formula (V) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:

R ^{4 is} selected from H, F, CI or methyl;

R ⁵ is H or methyl, preferably H _;

, ο

X is selected from H, -(CH ₂ ) ₃ -S(=0)2-CH ₃ , U ,

In a preferred embodiment of the invention, the invention relates to a compound selected from, but not limited to:

a compound according to the invention, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein The salt described in the pharmaceutically acceptable salt is selected from, but not limited to, sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethyl Base ammonium salt, Diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt, methylpyridine salt, 2,6- Dimethylpyridine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine salt, N-ethyl piperidine salt, polyamine resin Salt, phenicillin salt or a combination thereof. Preferred are sodium salts, potassium salts, ammonium salts, triethylamine salts, ethanolamine salts, diethanolamine salts, or combinations thereof. The invention also relates to a method of synthesizing the compounds. Those skilled in the art will recognize that the compounds of the present invention can be synthesized by a variety of methods of preparation. Preferred methods include, but are not limited to, the methods described below. Those skilled in the art will appreciate that the functionality exhibited on the molecule should be consistent with the planned transformation. In order to obtain the desired compound of the present invention, a judgment is sometimes required to change the order of the synthesis steps or to select a particular process scheme. Reasonable protecting groups are selected for the protection of reactive functional groups present in the compounds described herein.

 The present invention relates to a process for the preparation of the compound of the formula ω, which may be selected from the first or second method comprising the following steps, the method 1 comprising:

通式 （I-aO化合物通过克莱门森还原、 改进的克莱门森还原、 沃尔夫-凯惜纳还原、 黄鸣 龙还原或者以还原剂-路易斯酸组合方法还原羰基得到通式 （I-a)化合物 （当所述环 B带有取 代基时， 可先还原羰基再引入取代基后得到通式 （I-a)化合物， 或先引入取代基再还原同样得 到 (I-a)) ；

The general formula (Ia-aO compound is obtained by Clemson reduction, modified Clemson reduction, Wolf-Keithner reduction, Huangminglong reduction or reduction of carbonyl by reducing agent-Lewis acid combination method to obtain the general formula (Ia) a compound (when the ring B carries a substituent, the carbonyl group may be first reduced to introduce a substituent to obtain a compound of the formula (Ia), or the substituent may be introduced and then reduced to obtain (Ia));

通式 （I-a)化合物与通式 （I-b)化合物发生 suzuki偶联反应， 得到的产物进一步在还原剂 作用下加氢还原得 通式 (I-c)化合物；

The compound of the formula (Ia) is subjected to a suzuki coupling reaction with the compound of the formula (Ib), and the obtained product is further hydrogenated by a reducing agent to obtain a compound of the formula (Ic);

通式 （I-c)化合物发生 S_N2反应得到通式 （I-d)化合物;

The compound of the formula (Ic) undergoes an S _N 2 reaction to give a compound of the formula (Id);

 (l-d)

 The product obtained by the Mistunobu reaction of the compound of the formula (I-d) with the compound of the formula (I-e) is further hydrolyzed to give a compound of the formula (I).

 Method Two:

(l-ai) (la ₂ )

a compound of the formula (Ia ₂ ) obtained by reducing a carbonyl group by a reducing agent to obtain a compound of the formula (Ia ₂ ); or a formula (I-aO for reducing a carbonyl group to a hydroxyl group by a reducing agent and then undergoing a nucleophilic substitution reaction to obtain a formula ( 1-) compound;

The compound of the formula (Ia ₂ ) is reduced to give a compound of the formula (Ia); or the compound of the formula (1) is reduced to give a compound of the formula (Ia);

 The compound of the formula (I-a) is subjected to a suzuki coupling reaction with the compound of the formula (I-b), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (I-c);

(lc) (ld) The compound of formula Ic) undergoes an S _N 2 reaction to give a compound of the formula (Id);

通式 （I-d)化合物与通式 （I-e)化合物发生 Mistunobu反应得到的产物， 再进一步水解得 到通式 （I)化合物。

The product obtained by the Mistunobu reaction of the compound of the formula (Id) with the compound of the formula (Ie) is further hydrolyzed to give a compound of the formula (I).

cT^eF3或者 άV ³ , wherein R ⁹ or R ¹² are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy,

cT ^eF3 or ά

R ^{1U is} selected from the group consisting of ruthenium, F, Cl, Br, I, hydroxy, d- ₆ fluorenyl or d- ₆ methoxy, X, Y, ring B, R, R ¹ , R ² , R ³ , R ⁴ , The definitions of R ⁵ , R ⁶ , p, q and t are consistent with the definition of formula (I).

 More specifically, the method for preparing the compound of the formula (I) of the present invention, the method one comprises:

Using acetic acid, trifluoroacetic acid, hydrochloric acid/tetrahydrofuran as solvent, under the action of zinc powder or zinc amalgam, the formula (Ia reduces the carbonyl group to obtain the compound of the formula (Ia); or ethylene glycol, ethylene glycol dimethyl ether, poly Ethylene glycol as a solvent, in the presence of potassium hydroxide, sodium hydroxide, potassium t-butoxide, sodium t-butoxide, hydrazine hydrate, anhydrous hydrazine, the carbonyl group is reduced by the formula (I- _ai ) to obtain a compound of the formula (Ia) Or by using hydrazine, hydrazine-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide as solvent, in the presence of aluminum trichloride and zinc dichloride, the general formula (I-aO reduced carbonyl group) a compound of the formula (Ia). In the presence of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, sodium carbonate or potassium phosphate, palladium catalyst The compound of the formula (Ia) is subjected to a suzuki coupling reaction with the compound of the formula (Ib), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (Ic), wherein the palladium catalyst is selected from the group consisting of four Palladium triphenylphosphine, palladium dichloride, palladium acetate or Bis(triphenylphosphine)palladium dichloride, the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, zinc borohydride, cyanide Sodium borohydride, potassium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, sodium thioborohydride or lithium tri-sec-butylborohydride; ruthenium, osmium-dimethylformamide, tetrahydrofuran or The dimethyl sulfoxide is a solvent, heated under reflux in the presence of potassium carbonate or cesium carbonate, and the compound of the formula (Ic) is subjected to S _N 2 reaction to obtain a compound of the formula (Id); with methylene chloride or tetrahydrofuran as a solvent, a product obtained by the Mistunobu reaction of a compound of the formula (Id) with a compound of the formula (Ie) in the presence of diisopropyl azodicarboxylate or 1,1-(azodicarbonyl)dipiperidine under butylphosphine conditions Further hydrolyzed to give a compound of the formula (I).

 Method two includes:

(l- _ai ) (la ₂ ) (l-ai

 the fourth step

dd) (i) under the action of a reducing agent, the general formula (i- _ai) reduction of the carbonyl group to a hydroxyl group of general formula (1) compounds; or a reducing agent in the general formula (I- _ai) reduction of the carbonyl group to a hydroxyl group, Then using methylene chloride, hydrazine, hydrazine-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide as solvent, in the presence of triethylamine, pyridine, hydrazine, hydrazine-diisopropylethylamine, further with three The fluoromethanesulfonic anhydride reaction is further nucleophilically substituted with an iodo reagent to obtain a compound of the formula (Ia ₂ ); or under the action of a reducing agent, the formula (I-aO reduces the carbonyl group to a hydroxyl group, and then benzene, toluene, tetrahydrofuran, dichloro Methyl hydrazine, chloroform or 1,2-dichloroethane as a solvent, in the presence of triphenylphosphine / imidazole, nucleophilic substitution reaction with iodine element to obtain a compound of the formula (Ia ₂ ); with benzene, toluene, tetrahydrofuran, Dichloromethane, hydrazine, hydrazine-dimethylformamide, dimethyl sulfoxide, chloroform or 1,2-dichloroacetic acid as solvent, in aluminum trichloride, zinc dichloride, trifluoroacetic acid, acetic acid In the presence of hydrochloric acid, lithium aluminum hydride, triethyl silicon, sodium borohydride, general formula Ia ₂₎ reduction of hydroxy compound to give a compound of formula (Ia); or as benzene, toluene, tetrahydrofuran, of dichloromethane, Ν, Ν- dimethylformamide, dimethyl sulfoxide, chloroform or 1,2 Dichloroethane is a solvent, lithium aluminum hydride, triethyl silicon, sodium borohydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, and the compound of the formula (Ia ₂ ) is reduced in halogen to obtain the formula ( Ia) compound. In the presence of toluene/ethanol/water, acetonitrile/water, 1,4-dioxane/water or tetrahydrofuran/water as solvent, potassium carbonate, sodium carbonate or potassium phosphate, under the action of palladium catalyst The compound of the formula (Ia) is subjected to a suzuki coupling reaction with a compound of the formula (Ib), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (Ic), wherein the palladium catalyst is selected from tetratriphenyl Phospho palladium, palladium dichloride, palladium acetate or bis(triphenylphosphine)palladium dichloride, the reducing agent is selected from sodium borohydride, boron hydride Potassium, zinc borohydride, sodium cyanoborohydride, potassium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, sodium thioborohydride or lithium tri-sec-butyl borohydride; Dimethylformamide, tetrahydrofuran or dimethyl sulfoxide as a solvent, heated under reflux in the presence of potassium carbonate or cesium carbonate, the compound of the formula (Ic) is subjected to S _N 2 reaction to obtain a compound of the formula (Id); Methylhydrazine or tetrahydrofuran as solvent, tributylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl;)dipiperidine, compound of formula (Id) and formula Ie) The compound obtained by the Mistimobu reaction is further hydrolyzed to obtain a compound of the formula (I), wherein R ⁹ or R ¹² are each independently selected from H, F, Cl, Br, I or a hydroxyl group, and R ^{1Q is} selected from H, F, Cl, Br, I, hydroxy, d- ₆ fluorenyl or d- ₆ methoxy, X, Y, ring B, R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , The definitions of p, q and t are consistent with the definition of formula (I). The present invention also relates to a pharmaceutical composition comprising: an effective amount of a compound of the formula (I) or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, A pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient; the composition may further comprise one or more additional therapeutic agents. Other therapeutic agents described therein include:

 (a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or

 (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or

 (c) an SGLT-2 inhibitor or a pharmaceutically acceptable salt, and/or

(d) a PPAR _T agonist or a _{γ γ} partial agonist or a pharmaceutically acceptable salt, and/or

 (e) a PPAR^ dual agonist or pharmaceutically acceptable salt, and/or

(; f) a PPAR _s agonist or pharmaceutically acceptable salt, and/or

 (g) insulin or pseudo-insulin or a pharmaceutically acceptable salt, and / or

 (h) a protein tyrosine phosphatase-IB (PTP-1B) inhibitor or a pharmaceutically acceptable salt, and/or

 (i) a sulfonylurea inhibitor or a pharmaceutically acceptable salt, and/or

 (D a-glucosidase inhibitor or pharmaceutically acceptable salt, and/or

 (k) a GLP-K GLP-1 analog, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or

 (1) a glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or

 (m) anti-inflammatory drugs, and / or

 (n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or

 (0) diet pills, and / or

 (p) A drug for improving lipid distribution in a patient selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, niacin or a salt thereof, ? Enter! An agonist, a cholesterol absorption inhibitor, an acyl-CoA (cholesterol acyltransferase (ACAT)) inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or

 (q) biguanide, thiazolyldione, linnaphine, or a pharmaceutically acceptable salt or prodrug thereof.

In a preferred embodiment of the invention, the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrates (TAK-875) or a pharmaceutical thereof An acceptable salt or prodrug. The DDP-IV inhibitor is selected from the group consisting of linagliptin (lilastetine), omarigliptin

(MK-3102), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin (卡格Lenin), Melogliptin (Merolidine), Dutogliptin (Digliptin), Teneligliptin (Teliglitin), Gemigliptin (Ziglitin) or Trelagliptin (Tragliptin). The SGLT-2 inhibitor is selected from the group consisting of Dapagliflozin, Canagliflozin, Atigliflozin, Empagliflozin, Ipragliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin or Ertugliflozin; PPAR _Y agonists include Ciglitazone (cycloglitazone) ), Troglitazone (troglitazone), Pioglitazone (pioglitazone), Rosiglitazone (Rosiglitazone), Englitazone (englitazone), Darglitazoan (daglitazone), the PPAR^ dual agonist including mulaglitazar Gutazole or aleglitazar, the PPAR _S agonist comprises pioglitazone (pioglitazone;) or rosiglitazone (rosiglitazone). The biguanide therapeutic agent is selected from the group consisting of metformin or dibiguanidine. The thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, faglitazone or dapaglitazone. The sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, glibenclamide, glibenclamide, gliclazone, glipizide, or gliclazide. The levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide. The (X-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose or miglitol. The GLP-1 analogue is selected from Exenatide or Liraglutide. Larupeptide).

 The invention further relates to the use of the compound or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof, or medical use thereof Specifically, in the preparation of a G protein coupled receptor 40 agonist, in particular as a G protein coupled receptor 40 agonist, in the preparation of a pharmaceutical preparation, preferably for the treatment and/or prevention of metabolic diseases Use in applications. The metabolic diseases include diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, high glycerol Acidemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketoacidosis, fatty acid or glycerol High levels, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae angina, limp, heart disease One or more of seizures or strokes, further preferably including type II diabetes.

 The present invention also relates to a method of treating and/or preventing the above metabolic diseases, which comprises administering to a subject an effective amount of a compound of the present invention or a stereoisomer, hydrate, ester, solvate, co-crystal thereof. , a metabolite, a pharmaceutically acceptable salt or prodrug or a pharmaceutical composition of the invention.

 Terms used in the specification and claims have the following meanings unless stated to the contrary.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur involved in the groups and compounds of the present invention. Or nitrogen optionally further one or more of them correspond Substituted by isotopes, carbon isotopes include ¹² C, ¹³ C, and ¹⁴ C. Hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen), helium (T, also known as super heavy hydrogen; I, oxygen The isotopes include ¹⁶ 0, ¹⁷ 0 and ¹⁸ 0, the sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, the nitrogen isotopes include ¹⁴ N and ¹⁵ N, and the fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine. Isotopes include ³⁵ C1 and ³⁷ C1, and the isotopes include ⁷ 3⁄4r and ⁸¹ Br.

"Mercapto" refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 8 carbon atoms, more preferably a fluorenyl group of 1 to 6 carbon atoms, further A fluorenyl group of 1 to 4 carbon atoms is preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl -2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3- Dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl and various branched isomers thereof; the thiol group may optionally be further Up to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ^U , nitro, cyano, isocyano, alkenyl, alkynyl , embankment group, a hydroxyl group embankment, embankment group, a carbocyclic group, a heterocyclic group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl,

-(CH ₂ ) _m -C(=0)-0-R ^u , -(CH ₂ ) _m -C(=0)-NR ¹¹ R ^lla , -(CH ₂ ) _m -S(=0) _n - Substituting R ^u , —0-C(=0)-0-R ⁿ or a substituent of —NR ¹¹ R ^{l la} , wherein R ¹¹ and R ^la are each independently selected from H, hydroxy, amino, carboxy, d— alkyl with _{8, 8} embankment D- group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl group, 3-10 yuan carbocyclyl 4 to 10-membered heterocyclic, 3-10 yuan carbocyclyl group Or a 4- to 10-membered heterocyclyloxy group, m is selected from 0, 1, 2, 3, 4 or 5, and n is selected from 0, 1 or 2. The thiol group, R ^{11 ŒR lla} , which appears herein, is as defined above.

 "Alkoxy" means -0-fluorenyl, non-limiting examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl- 1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy Base, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy.

 "Alkenyl" means a straight or branched unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably Alkenyl of 2-8 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, Hepten-2-yl, hepten-3-yl, hept-4-yl, oct-3-yl, nonen-3-yl, nonen-4-yl and undecen-3-yl. The alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.

 "Alkynyl" means an alkynyl group having 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkynyl group of 2-8 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, butyn-1-yl, butyn-3-yl, pentyn-1-yl, hexyn-1-yl, heptyn-1-yl , heptyn-3-yl, heptyn-4-yl, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4- base. The alkynyl group may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.

。 所述的碳环基可以任选进一步被 0至 8个选自 F、 Cl、 Br、 I、 =0、"Carbocyclyl" means a saturated or unsaturated aromatic or non-aromatic ring, and an aromatic or non-aromatic ring may be 3 to 10 a monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, phenyl, 1-cyclohexyl-2-alkenyl, 1- Cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, decyl, cyclodecyl, cyclododedecyl, phenyl, naphthyl, anthracenyl, phenanthryl,

. The carbocyclic group may be further optionally from 0 to 8 selected from the group consisting of F, Cl, Br, I, =0,

-CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ^U , nitro, cyano, isocyano, alkenyl, alkynyl, fluorenyl, hydroxyindenyl, decyloxy, carbocyclyl, heterocyclyl, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R u, - (CH 2) m -C (= 0) -0-R ^u , -(CH ₂ ) _m -C(=0)-NR ^u R ^{l la} , -(CH ₂ ) _m -S(=0) _n -R ^u , -0-C(=0)-0-R Substituted by a substituent of ⁿ or -NR ^u R ^{l la} , m is selected from 0, 1, 2, 3, 4 or 5, and n is selected from 0, 1 or 2. The carbocyclic group appearing herein is as defined above.

 "Heterocyclyl" means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 4 heteroatoms or groups selected from N, 0 or S (=0;»n, preferably 4 to 8 membered heterocyclic groups, optionally substituted in the ring of the heterocyclic group N, S can be oxidized to various oxidation states. The heterocyclic group can be attached to a hetero atom or a carbon atom, and the heterocyclic group can be bonded to a bridged or spiro ring, non-limiting examples include epoxy ethyl, epoxy Propyl, azacyclopropyl, oxetanyl, azetidinyl, thiot-butyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3 - dioxolyl, azepanyl, oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, High piperidinyl, furyl, thienyl, pyranyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperid Ding , morpholinyl, thiomorpholinyl, thiazolidine, 1,3-dithia, dihydrofuranyl, dihydropyranyl, dithiapentanyl, tetrahydrofuranyl, tetrahydrothiophenyl, Tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzo Dihydrofuranyl, 2-pyrroline, 3-pyrroline, indanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, Pyrazolinyl, dithiazinyl, dithiadecyl, dihydrothienyl, pyrazolyl imidazolinyl, imidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, 3- Azabicyclo[3丄0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-decylquinazinyl, N-pyridylurea, 1, 1-dioxythiomorpholinyl, azabicyclo[3.2.1], azabicyclo[5.2.0]decyl, oxatricyclo[5.3.1.1]

所述的杂 环基可以任选进一步被 0至 8个选自 F、 Cl、 Br、 I、 =0、 -CH₂F、 -CHF₂、 -CF₃、 羟基、 -SR^U、 硝基、 氰基、 异氰基、 烯基、 炔基、 垸基、 羟基垸基、 垸氧基、 碳环基、 杂环基、 C₂— ₈烯基、 C₂.₈ 炔 基 、 -(CH₂)_m-C(=0)-R^u 、 -(CH₂)_m-C(=0)-0-Rⁿ 、 -(CH₂)_m-C(=0)-NRⁿR^{l la} 、 -(CH₂)_m-S(=0)_n-R^u、 -0-C(=0)-0-R^u或者 -NR^uR^lla的取代基所取代， m选自 0、 1、 2、 3、 4 或者 5， n选自 0、 1或者 2。 本文中出现的杂环基， 其定义如上所述。 "氨基 "是指 -NH₂。 Twelve fluorenyl, aza-gold sulfhydryl, oxaspiro[3.3]heptanyl,

The heterocyclic group may be further optionally 0 to 8 selected from the group consisting of F, Cl, Br, I, =0, -CH ₂ F, -CHF ₂ , -CF ₃ , hydroxy, -SR ^U , nitro, a cyano group, an isocyano group, an alkenyl group, an alkynyl group, embankment group, a hydroxyl group embankment, embankment group, a carbocyclic group, a heterocyclic group, C ₂ - ₈ alkenyl, C _{2 8} alkynyl, -. (CH _{2 m} -C(=0)-R ^u , -(CH ₂ ) _m -C(=0)-0-R ⁿ , -(CH ₂ ) _m -C(=0)-NR ⁿ R ^{l la} , - Substituting (CH ₂ ) _m -S(=0) _n -R ^u , -0-C(=0)-0-R ^u or -NR ^u R ^lla , m is selected from 0, 1, 2 3, 4 or 5, n is selected from 0, 1 or 2. The heterocyclic group appearing herein is as defined above. "Amino" means -NH ₂ .

"Cyano" means "^N" .

" ^Isocyano " refers to divination ^G_ .

"Nitro" means -N0 ₂ .

 "Hydroxy" means -OH.

 "巯基" means -SH.

 "Acid group" means -C(=0)H.

 "Carboxy" means -COOH.

 "=0" is a commonly used practice in the art and refers to an oxygen atom connected by a double bond, such as a double bond oxygen atom to a carbon atom in a carbonyl group.

 "Hydroxymethane" means a fluorenyl group substituted by 1, 2 or 3 hydroxy groups, and the fluorenyl group is preferably a C1-4 fluorenyl group. Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl.

 "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid, and the free acid is reacted with a non-toxic inorganic or organic base. The salt obtained. Non-limiting examples of the inorganic base include sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium; non-limiting examples of the organic base include ammonia, trimethylamine, tetramethylammonium, Diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, proca Cause, choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt.

 "Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

 "Excipient" means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.

 An "adjuvant" is a non-specific immunopotentiator that, when injected with an antigen or pre-injected into the body, enhances the body's immune response to the antigen or alters the type of immune response.

 "Diluent" is also called "filler". When the original drug is processed into a powder, or to facilitate the spraying of the added inert substance to be diluted. Such as: clay, kaolin, clay, talcum powder, etc.

"Prodrug" means a compound of the invention that can be converted to biological activity by metabolism in vivo. Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound. Prodrugs include compounds formed by attachment of a carboxy group of any of the compounds of the present invention to any group. When a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free carboxyl group, respectively. Examples of prodrugs include, but are not limited to, A compound formed by a carboxyl functional group in the compound of the present invention and methanol, ethanol or benzyl alcohol.

 "eutectic" refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bond, wherein the pure state of API (active pharmaceutical ingredient) and CCF (eutectic formation) They are all solid at room temperature and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate. Non-limiting examples of the "eutectic former" include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, Threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid Acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonate Acid, formic acid, fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid , pantothenic acid, stearic acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid , p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or trifluoro Methanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-two Ethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phenylephrine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine , hydrazine, piperazine, piperidine and N-ethylpiperidine.

 "Stereoisomer" refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.

 "Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, including where the event or condition occurred and What happened. For example, "heterocyclic group optionally substituted by a thiol group" means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group Happening.

 "Pharmaceutical composition" means a combination of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, or/and one or more additional therapeutic agents, and a pharmaceutically acceptable form. Agents, adjuvants, diluents and carriers.

The "EC ₅₀ " half effective concentration refers to the concentration at which half of the maximum efficacy is reached. Detailed ways

 The embodiments of the present invention and the beneficial effects thereof are described in detail below by way of specific examples, which are intended to provide a better understanding of the nature and characteristics of the present invention.

 The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shift (δ) to

The unit of 10" ⁶ (ppm) is given.

NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDC1 ₃ ), deuterated methanol (CD ₃ OD). ), the internal standard is tetramethylsilane (TMS). For the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

 The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 4.6 mm). The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ~ 0.20 mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4 mm. ~ 0.5 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as carrier.

 The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.

 The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.

 The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

 The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

 Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.

 There is no particular description in the examples, and the solution means an aqueous solution.

 There is no particular description in the examples, and the reaction temperature is room temperature.

 Room temperature is the optimum reaction temperature, which is 20 ° C ~ 30 ° C.

 Other symbols used in this article have the following meanings:

 S: single peak;

 d: doublet;

 t: triplet;

 q: four peaks;

 m: multiple peaks;

 Br: broad peak;

 Hz: Hertz;

 Bn: benzyl;

 Me: methyl;

 Et: ethyl;

 Ts: p-toluenesulfonyl;

 TBS: tert-butyldimethylsilyl. Intermediate 1 : 5-[3-(Hydroxymethyl)phenyl]-4-methyl-bicyclo [4.2.0] octyl-1,3,5-tris-2-propanol (lm)

5-[3-(hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol

第一步： 2-苄氧基 -4-甲基 -1-硝基苯（lb)

First step: 2-benzyloxy-4-methyl-1-nitrobenzene (lb)

 2-benzyloxy-4-methyl- 1 -nitro-benzen

 5-Methyl-2-hydroxy-1-nitrobenzene (51.04 g, 333 mmol) was dissolved in acetonitrile (300 mL), then benzyl bromide (57.00 g, 333 mmol) and potassium carbonate (92.13 g, 666 mmol), heated to reflux for 1.5 h, filtered, EtOAcjjjjjjjjjjjj .

3⁄4 NMR (300 MHz, CDC1 ₃ ) δ 7.81 (d, 1Η), 7.56― 7.30 (m, 5H), 6.93 (s, 1H), 6.83 (d, 1H), 5.22 (s, 2H), 2.39 (s , 3H).

 Step 2: 2-Benzyloxy-4-methylaniline (lc)

2-benzyloxy-4-methyl-aniline

 Iron powder (10.39 g, 186 mmol) and ammonium chloride (2.16 g, 40 mmol) were dissolved in a mixed solution of ethanol (150 mL) and water (150 mL), heated to reflux for 15 minutes, and added to the reaction flask. -benzyloxy-4-methyl-1-nitrobenzene lb (15.08 g, 62 mmol), EtOAc (EtOAc) The organic layer was dried (MgSO4), evaporated

 The third step: 2-oxy-1-bromo-4-methyl-benzene (Id)

 2-benzyloxy- 1 -bromo-4-methyl -benze

 2-Benzyloxy-4-methylaniline lc was dissolved in acetone (80 mL), and hydrobromic acid solution (45 mL, hydrobromic acid content w/w = 48%) was added to the ice salt bath. Slowly add a solution of sodium nitrite (4.22 g, 61.21 mmol) in water (20 mL), stir for 10 minutes, slowly add dropwise copper bromide (5.18 g, 64.00 mmol) in hydrobromic acid (10 mL, hydrogen The bromic acid content w/w = 48%), the temperature was raised to 75 ° C and stirred for 2.5 hours, and the mixture was cooled to room temperature, and brine (100 mL) was added, and extracted with ethyl acetate (100 mL×2). Drying over anhydrous sodium sulfate, EtOAc (EtOAc m.) -1-Bromo-4-methyl-benzene Id (2.94 g, yield 89.8%)

 The fourth step: 1,1-diethoxyethylene (If)

 1 , 1 -diethoxyethene

CH ₂

 . people.

 Add bromoacetaldehyde diethyl diol le (58.80 g, 29.84 mmol, Astatech) and octadecyl hexaether to the reaction flask.

(1.59 g, 6.00 mmol) and anhydrous tetrahydrofuran (200 mL), potassium tert-butoxide (34.20 g, 30.48 mmol) was added at 0 ° C, stirred for 2 hours in an ice bath, filtered, atmospheric distillation, collected at 130 ° C The tetrahydrofuran and tert-butanol fractions were distilled under reduced pressure to give 1,1-diethoxyethylene If (15.00 g, yield 43.3%).

3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 3.83 - 3.73 (m, 4H), 3.04 (d, 2H), 1.33 - 1.24 (m, 6H).

Step 5: 5-Benzyloxy-3-methyl-bicyclo[4.2.0]octyl-1,3,5-trien-7-one (lg) 5-benzyloxy-3-methyl-bicyclo[4.2.0]o 7-one

2-Benzyloxy-1-bromo-4-methylbenzene Id was dissolved in tetrahydrofuran (150 mL), followed by sodium amide (4.5 g, 115.5 mmol) and 1,1-diethoxyethylene If (13.4) g, 115.5 mmol), heated under reflux for 20 hours. The reaction solution was poured slowly into ice water (100 mL), and then added 12 mol/L of concentrated hydrochloric acid (5 mL). to give a yellow oil of 5-benzyloxy -:; mL x 2), organic phases were combined and concentrated (1 »= 100 n-hexyl embankment / ethyl acetate (v / _V) under reduced pressure, the residue was separated and purified by silica gel column chromatography 3-Methyl-bicyclo[4.2.0]octane-1,3,5-trien-7-one lg (2.01 g, yield 16.0%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.44 (d, 2Η), 7.40― 7.31 (m, 3H), 6.87 (s, 1H), 6.71 (s, 1H), 5.44 (s, 2H), 3.87 (s , 2H), 2.38 (s, 3H).

 Step 6: 5-Benzyloxy-2-bromo-3-methyl-bicyclo[4.2.0]octyl-1,3,5-triene-7-one (lh)

 5-benzyloxy-2-bromo-3-methyl-bicycl -l,3,5-trien-7-one

5-Benzyloxy-3-methyl-bicyclo[4.2.0]oct-1,3,5-trien-7-one lg (2.00 g, 8.40 mmol) was dissolved in glacial acetic acid (150 mL). Benzyltrimethylammonium tribromide (PhCH ₂ N ⁺ (CH ₃ ) ₃ Br ₃ -, 3.59 g, 9.24 mmol) and zinc chloride (1.34 g, 10.08 mmol) were added successively, and stirred at room temperature for 6 hours. An aqueous solution of sodium sulfite (100 mL, Na ₂ S0 _{3 W} / w = 5%;) was obtained, and the mixture was extracted with ethyl acetate (50 mL x 2). Purification (n-hexane/ethyl acetate (ν/ν) = 80: 1) afforded 5-benzyloxy-2-bromo-3-methyl-bicyclo[4.2.0] sin-1,3 as a yellow oil. 5-Trien-7-one lh (2.02 g, yield 76.0%).

3⁄4 NMR (300 MHz, DMSO- ₆ ) δ 7.69 (d, 1H), 7.47 - 7.37 (m, 4H), 6.93 (d, 1H), 5.38 (s, 2H), 3.99 (s, 2H), 2.51 ( s, 3H).

 Step 7: 2-Benzyloxy-5-bromo-4-methyl-bicyclo[4.2.0]octyl-1,3,5-triene (li)

2-benzyloxy-5-bromo-4-methyl-bicyclo[4.2.0]octa-l,3,5-triene

 Dissolve 5-benzyloxy-2-bromo-3-methyl-bicyclo[4.2.0]oct-1,3,5-trien-7-one 1h in glacial acetic acid (100 mL), add zinc powder (2.05 g, 31.5 mmol), heated to 60 ° C, stirred for 6 hours, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjj The 2-benzyloxy-5-bromo-4-methyl-bicyclo[4.2.0]oct-1,3,5-triene li (2.02 g, yield 76.0%) was obtained as a yellow oil.

 Step 8: 3-(2-Benzyloxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-benzaldehyde (lj)

 3-(2-benzyloxy-4-methyl-5-bicy -l,3,5-trienyl)benzaldehyde

2-Benzyloxy-5-bromo-4-methyl-bicyclo[4.2.0]oct-1,3,5-triene li (600 mg, 1.98 mmol) was dissolved in toluene (15 mL), water (15 In a mixed solution of mL) and ethanol (3 mL), 3-formylbenzeneboronic acid (330 mg, 2.17 mmol), potassium carbonate (550 mg, 3.96 mmol) and tetrakis(triphenylphosphine)palladium (8 mg) were added in sequence. , 0.05 mmol), heated to 90. C The reaction was stirred for 8 hours, extracted with ethyl acetate (50 mL x 2), organic phases were combined and concentrated under reduced pressure, the residue was separated by silica gel column chromatography (n-hexyl embankment / ethyl acetate _{(v / V; »= 20} : l), 3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0] oct-1,3,5-triene)-benzaldehyde lj (201 mg, yield) 31.0%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 10.05 (s, 1Η), 7.81 (t, 2H), 7.59― 7.53 (m, 2H), 7.51― 7.36 (m, 5H), 6.76 (s, 1H), 5.20 (s, 2H), 3.28 - 3.18 (m, 2H), 3.12 - 3.04 (m, 2H), 2.25 (s, 3H).

 Step 9: [3-(2-Benzyloxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-phenyl]methanol (lk)

 [3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methanol

 3-(2-Benzyloxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3-ene)-benzaldehyde lj (0.20 g, 0.61 mmol) was dissolved in methanol

(40 mL), sodium borohydride (46 mg, 1.22 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of saturated ammonium chloride (5 mL) was evaporated. (n-hexane/ethyl acetate (ν/ν) = 10: 1) to give [3-(2-oxy-4-methyl-5-bicyclo[4.2.0] sin-1,3 as a white solid. ,5-triene)-phenyl]methanol lk (0.19 g, yield 95.0%)

 Step 10: 5-[3-(Hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]octyl-1,3,5-trien-2-ol (lm)

5-[3-(hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol

 Dissolve [3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-phenyl]methanol lk (0.19 g, 0.58 mmol) Palladium/carbon (0.10 g, palladium content w/w = 10%) was added to methanol (50 mL) under a hydrogen atmosphere at room temperature for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. (petroleum ether/ethyl acetate (v/v) = 5: 1) to give 5-[3-(hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]oct-1 as a white solid. 3,5-Trien-2-ol lm (0.13 g, yield 93.0%).

^ NMR (400 MHz, CDC1 ₃ ) δ 7.40 (t,lH), 7.31 (d, 2H), 7.23 (d, IH), 6.61 (s, IH), 4.74 (s, 2H), 3.07 (m, 4H) ), 2.24 (s, 3H). Intermediate 2: (S)-2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester (2d)

 -methyl-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate

 2-(6-Hydroxybenzofuran-3-yl)acetic acid (200 g, 1.04 mol) was dissolved in methanol (1.2 L), triethylamine (13 ml, 0.1 mol), palladium/carbon (20 g, Palladium content w/w = 10%), after replacing hydrogen, it was reacted at room temperature for 24 hours. Filtration, the filtrate was concentrated, and the residue was crystallised eluted with ethyl acetate (1L), EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The residue was recrystallized from methylene chloride to afford 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid (180 g, yield: 90%).

3⁄4 NMR (400 MHz, DMSO-d ₆ ) δ 12.28 (s, IH), 9.24 (s, IH), 6.97 (d, IH), 6.23 (dd, IH), 6.15 (d, IH), 4.64 (t , IH), 4.14 (dd, IH), 3.62 (m, IH), 2.65 (dd, IH), 2.45 (dd, IH).

 Step 2: (S)-2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid (R)-l-phenethylamine salt (2b)

(R)- 1 -phenylethanaminium (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate

 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid 2a (9.32 g, 48 mmol) was dissolved in acetone (80 mL) and heated to reflux to give R-benzene An acetone solution of ethylamine (2.91 g, 24 mmol, 13 mL) was slowly added dropwise to the reaction solution. After the completion of the dropwise addition, the heating was stopped, and the temperature was naturally lowered to room temperature, and the mixture was stirred overnight. Filtration, the solid was suspended in a mixed solution of ethyl acetate and water, 1M diluted hydrochloric acid was added dropwise to the filtrate pH < 2, extracted with ethyl acetate, concentrated under reduced pressure, and the concentrate was dissolved in acetone (35 mL). An acetone solution of R-phenylethylamine (1.53 g, 12.7 mmol) was slowly dropped into the reaction solution while heating to reflux. After the completion of the dropwise addition, the heating was turned off, and the temperature was naturally lowered to room temperature, and the mixture was stirred overnight. After filtration, the precipitate was washed with a small amount of acetone, and the precipitate was dissolved in acetone (25 mL) to recrystallize to give (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl; R -l-phenethylamine salt 2b (600 mg, 60%)

 Step 3: (S) -2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid (2c)

 (S)-2-(6-hydroxy-2,3-dihydrobenz

 (S)-2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl;)acetic acid (R-1 -phenylethylamine salt 2b) was dissolved in 1M hydrochloric acid and ethyl acetate 50 mL 3), the organic layer was dried over anhydrous sodium sulfate and evaporated 99%).

 Step 4: (S)- 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester (2d)

 (S)-methyl-2-(6-hydroxy-2,3-dihy e

 (S)-2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid 2c was dissolved in methanol at room temperature, concentrated sulfuric acid (0.2 mL) was added dropwise, and the mixture was warmed to 50 ° C After the reaction for 2 hours, the reaction was quenched with EtOAc (EtOAc) (EtOAc) /ethyl acetate (v/v) = 30: 1), (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 2d as a white solid. 317 mg, 80%, ee% = 99%).

 Intermediate 3: 5-Bromo-4-methyl-bicyclo [4.2.0] octyl-1,3,5-trien-2-ol (3e)

5-bromo-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol third step

第一步： 5-苄氧基 -3-甲基 -双环 [4.2.0]辛 -1,3,5-三烯 -7-醇

First step: 5-benzyloxy-3-methyl-bicyclo[4.2.0]oct-1,3,5-trien-7-ol

 5-benzyloxy-3-methyl-bicyclo[4.2.0]octa-l,3,5-trien-7-ol

 5-Benzyloxy-3-methyl-bicyclo[4.2.0]oct-1,3,5-trien-7-one lg (10.0 g, 41.97 mmol) was dissolved in methanol (30 mL) and tetrahydrofuran ( In a mixed solution of 50 mL), sodium borohydride (3.18 g, 83.94 mmol) was added portionwise at 0 ° C, and the mixture was warmed to room temperature for 30 minutes after the addition. After the reaction was completed, the reaction was quenched with water (30 mL), EtOAc (EtOAc) Purification by ether to give 5-benzyloxy-3-methyl-bicyclo[4.2.0]oct-1,3,5-trien-7-ol 3a (9.35 g, yield 93%)

 Step 2: 5-Benzyloxy-7-iodo-3-methyl-bicyclo[4.2.0]octyl-1,3,5-triene (3b)

 5-benzyloxy-7-iodo-3-methyl-bicyclo[4.2.0]octa-l,3,5-triene

无水无氧处理， 氮气保护， 将碘（26.3 g , 103.62 mmol)加入到甲苯（120 mL) 中， 加入三 苯基膦（23.6 g,89.80 mmol), 搅拌 5分钟， 加入咪唑（14.1 g,207.23 mmol), 搅拌 10分钟， 将 5- 苄氧基 -3-甲基 -双环 [4.2.0]辛 -1,3,5-三烯 -7-醇 3a (8.3 g, 34.54 mmol)溶解到甲苯（40 mL) 中后 再加入到反应中， 室温下搅拌 1小时。 反应结束后， 加入饱和硫代硫酸钠水溶液（100 mL)， 搅 拌 5分钟。 分层后用石油醚萃取水层 （100 mL x 3)， 合并有机相， 无水硫酸钠干燥， 过滤， 将 滤液减压浓缩， 残留物用硅胶柱层析 （石油醚 /二氯甲垸（v/v) =20/l)得到淡黄色固体状的 5-苄 氧基 -7-碘 -3-甲基 -双环 [4.2.0]辛 -1,3,5-三烯 3b (9.9 g, 产率 82%)。

Anhydrous anaerobic treatment, nitrogen protection, iodine (26.3 g, 103.62 mmol) was added to toluene (120 mL), triphenylphosphine (23.6 g, 89.80 mmol) was added, stirred for 5 minutes, and imidazole (14.1 g, 207.23 mmol), stirred for 10 minutes, dissolved 5-benzyloxy-3-methyl-bicyclo[4.2.0]oct-1,3,5-trien-7-ol 3a (8.3 g, 34.54 mmol) Toluene (40 mL) was added to the reaction and stirred at room temperature for 1 hour. After completion of the reaction, a saturated aqueous solution of sodium thiosulfate (100 mL) was added and stirred for 5 min. After stratification, the aqueous layer was extracted with EtOAc (EtOAc)EtOAc. v/v) = 20/l) gave 5-benzyloxy-7-iodo-3-methyl-bicyclo[4.2.0]oct-1,3,5-triene 3b (9.9 g) as a pale yellow solid. , yield 82%).

 Step 3: 5-Benzyloxy-3-methyl-bicyclo[4.2.0]octyl-1,3,5-triene (3c)

 5-benzyloxy-3-methyl-bicyclo[4.2.0]octa-l,3,5-triene

Anhydrous anaerobic treatment, nitrogen protection, lithium tetrahydroaluminum (2.68 g, 70.67 mmol) was added to tetrahydrofuran (120 mL), 5-benzyloxy-7-iodo-3-methyl-bicyclo[4.2. 0] Oct-1,3,5-triene 3b (9.9 g, 28.26 mmol) was dissolved in tetrahydrofuran (180 mL), added dropwise to the reaction, and stirred at room temperature for 30 minutes. After the reaction is completed, the reaction mixture is slowly added with water (100 mL), and the mixture is evaporated to dryness. EtOAc (EtOAc) concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / of dichloromethane _{(v / V; »= 20} / l) to give a pale yellow solid of 5-benzyloxy-3-methyl - bicyclo [ 4.2.0] oct-1,3,5-triene 3c (6.27 g, yield: 98.9%).

3⁄4 NMR (400 MHz, DMSO-d ₆ ) δ 7.42 - 7.30 (m, 5H), 6.56 (s, 1H), 6.50 (s, 1H), 5.13 (s, 2H), 3.21 - 3.13 (m, 2H) , 3.06 - 2.96 (m, 2H), 2.22 (s, 3H).

 Step 4: 3-Methylbicyclo [4.2.0] octyl-1,3,5-triene-5-ol (3d)

3-methylbicyclo[4.2.0]octa-l,3,5-trien-5-ol

 Dissolve 5-benzyloxy-3-methyl-bicyclo[4.2.0]oct-1,3,5-triene 3c (49.0 g, 218, 42 mmol) in methanol (500 mL) with palladium on carbon (5.0 g, palladium content w/w = 10%), and reacted under a hydrogen atmosphere at 35 ° C for 20 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated, and then dichloromethane was purified to give 3-methylbicyclo[4.2.0] oct-1,3,5-trien-5-ol 3d (52.5 g, The rate is 93.9%).

 Step 5: 5-Bromo-4-methyl-bicyclo[4.2.0]octyl-1,3,5-trien-2-ol (3e)

5-bromo-4-methyl-bicyclo[4.2.0]octa-l,3,5-trien-2-ol

 3-Methylbicyclo[4.2.0]octyl-1,3,5-trien-5-ol 3d (22.0 g, 0.16 mol) and benzyltrimethylammonium tribromide (63.9 g, 0.16 mol) Dissolved in acetonitrile (600 mL) and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous solution of sodium thiosulfate (300 mL) was added and stirred for 30 min. The mixture was extracted with EtOAc (EtOAc EtOAc (EtOAc (MeOHMeOHMeOHMeOH Bicyclo [4.2.0] oct-1,3,5-trien-2-ol 3e (29.0 g, yield 84%).

3⁄4 NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1 Η), 6.55 (s, 1H), 2.93 (s, 4H), 2.21 (s, 3H). Example 1: 2-[6-[ [3-[4-methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy] -2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 1)

 2-[6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l ,3,5-trienyl]phenyl]meth oxy]-2,3- Dihydrobenzofuran-3-yl]acetic acid

第一步： 3-甲硫基丙基 -4-甲基苯磺酸 （1B)

First step: 3-methylthiopropyl-4-methylbenzenesulfonic acid (1B)

3-methylsulfanylpropyl 4-methylbenzenesulfonate

3-Methylthiopropyl-1-ol lA (20.0 g, 188 mmol, Demer) was dissolved in toluene (100 mL), and under nitrogen, Ν, Ν, Ν', Ν'--- Base-1,6-hexanediamine (3.25 g, 19 mmol) and triethylamine (40 mL, 277 mmol), ice bath A solution of p-toluenesulfonyl chloride (54.0 g, 283 mmol) in toluene (100 mL) was slowly added dropwise, and the mixture was stirred for 3 hrs in ice-bath, and extracted with ethyl acetate (100 mL x 2). Drying, filtration, and concentrating the filtrate under reduced pressure. EtOAc m. Sulfonic acid 1B (32.34 g, yield 67.0%).

 Step 2: 3-Methylsulfonylpropyl-4-methylbenzenesulfonic acid (1C)

3-methylsulfonylpropyl 4-methylbenzenesulfonate

 3-Methylthiopropyl-4-methylbenzenesulfonic acid 1B (12.2 g, 46.9 mmol) was dissolved in methanol (250 mL), stirred for 5 minutes in an ice bath, and potassium peroxodisulfate complex salt was slowly added dropwise ( 57.7 g, 93.8 mmol) of water (250 mL) solution, remove the ice bath, stir at room temperature for 20 hours, slowly pour the reaction into water (1 L), stir for 10 minutes, filter, dissolve the filter cake in dichloromethane The mixture was dried over anhydrous sodium sulfate (MgSO4), filtered and evaporated. %).

 Third step: [3-[4-methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl] Methanol (1D)

 [3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

 5-(3-(Hydroxymethyl)phenyl)-4-methyl-cyclo[4.2.0]octyl-1,3,5-trien-2-ol lm (0.16 g, 0.67 mmol, Intermediate 1) was dissolved in hydrazine, hydrazine-dimethylformamide (25 mL), 3-methylsulfonylpropyl-4-methylbenzenesulfonic acid 1C (0.11 g, 0.80 mmol) and cesium carbonate (0.26) g, 0.80 mmol), heated to 80 ° C, stirred for 2 hours, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjj [3-[4-Methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 1D (0.18 g, yield 75.0%).

 Step 4: 2-(6-Hydroxybenzofuran-3-yl)acetic acid (1F)

 2-(6-hydroxybenzofuran-3-yl)acetic acid

Ethyl chloroformate (28.00 g, 170 mmol) was dissolved in concentrated sulfuric acid at 0 ° C, resorcinol 1E (17.62 g, 160 mmol) was added, and reacted at room temperature for 2 hours, and the reaction solution was poured into ice. In water, the mixture was filtered, and the filter cake was washed with water (100 mL x 3) and dried. The filter cake was dissolved in 1M sodium hydroxide solution (1 L), heated to reflux for 2 hours, cooled to room temperature, and concentrated with sulfuric acid to dissolve the reaction mixture. Ethyl acetate (280 mL x 3) was extracted, the combined organic phases dried over anhydrous magnesium sulfate Concentration under reduced pressure gave 2-(6-hydroxybenzofuran-3-yl)acetic acid 1F (16.00 g, yield 52%).

 Step 5: 2-(6-Hydroxybenzofuran-3-yl;) methyl acetate (1G)

 Methyl 2-(6-hydroxybenzofuran-3-yl)acetate

 2-(6-Hydroxybenzofuran-3-yl)acetic acid 1F (16.00 g, 83.3 mmol) was dissolved in methanol (75 mL), concentrated sulfuric acid (8 mL) was added dropwise, and the mixture was heated to reflux for 4 hr. Concentrate under reduced pressure, add chloroform (300 mL), wash with water (100 mL×3), wash with brine (100 mL×3), The mixture was concentrated under reduced pressure. EtOAc EtOAcjjjjjjjj (8.37 g, yield 49%).

 Step 6: (2,3-Dihydrobenzofuran-3-yl;) Methyl acetate (1H)

 Methyl 2-(2,3-dihydrobenzofuran- -yl)acetate

 Methyl 2-(6-hydroxybenzofuran-3-yl)acetate 1G (7.38 g, 35.8 mmol) was dissolved in methanol (65 mL), palladium/carbon (1.38 g, palladium content w/w = 10 %), under a hydrogen atmosphere, at room temperature for 18 hours, filtered, and the filtrate was concentrated under reduced pressure. EtOAc mjjjjjjj Methyl 3-dihydrobenzofuran-3-yl)acetate 1H (4.50 g, yield 60.0%).

 Step 7: 2-[6-[[3-[4-Methyl-2-(3-methylsulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5- Methyltriphenyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (II)

 2-[6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]meth oxy]-2,3- Dihydrobenzo

[3-[4-Methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 1D ( 0.18 g, 0.5 mmol) dissolved in dichloromethane (30 mL), followed by (2,3-dihydrobenzofuran-3-yl;) methyl acetate 1H (0.13 g, 0.6 mmol), Phosphine (0.22 g, 1.1 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (0.28 g, 1.1 mmol), mp. Ether / ethyl acetate (v / _V ; » = l _: l) to get white 2-[6-[[3-[4-methyl-2-P-methylsulfonylpropoxy]; 5-5-cyclo[4.2.0]octyl-1,3,5- Methyltriene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate II (0.22 g, yield 78.0%).

 Step 8: 2-[6-[[3-[4-Methyl-2-(3-methylsulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5- Triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 1)

 2-[6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]meth oxy] -2,3- Dihydrobenzo

 2-[6-[[3-[4-methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5-triene] Methyl phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate II (0.21 g, 0.38 mmol) was dissolved in methanol (20 mL) and water (20 mL) Add sodium hydroxide (0.15 g, 3.82 mol), stir at room temperature for 1 hour, add 2M hydrochloric acid to pH 3, extract with ethyl acetate (20 mL×3), Purification by silica gel column chromatography (ethyl acetate) afforded 2-[6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy) -5-cyclo[4.2. 0] Xinzhi-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid compound 1 (0.13 g, yield 62.0%).

^ NMR (400 MHz, CDC1 ₃ ) δ 7.41 (t, lH), 7.34 (d, 2H), 7.23 (s, IH), 7.06 (d, IH), 6.62 (s, IH), 6.55 ― 6.45 (m , 2H), 5.06 (s, 2H), 4.77 (t, IH), 4.33 - 4.28 (m, IH), 4.26 (dd, J = 15.4, 5.7 Hz, 2H), 3.86 - 3.75 (m, IH), 3.30― 3.17 (m, 4H), 3.10― 3.03 (m, 2H), 2.97 (s, 3H), 2.81 (dd, lH), 2.62 (dd, lH), 2.32 (dt, 2H), 2.22 (s, 3H).

 Example 2: 2-[(3S)-6-[[3-[4-methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]-l,3, 5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 2)

 2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl] methoxy]-2 ,3-dihydrobenzofuran-3-yl]acetic acid

第一步： 2-[(3S)-6-[[3-[4-甲基 -2-(3-甲磺酰基丙氧基) -5-并环 [4.2.0]-1,3,5-三烯]苯基]甲氧 基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 （2B)

First step: 2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-cyclo[4.2.0]-1,3, Methyl 5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (2B)

 2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl] methoxy] -2 , 3-dihydrob

 [3-(4-Methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl)methanol 1D ( 0.21 g, 0.58 mmol) dissolved in dichloromethane (30 mL), followed by (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 2d (0.15 g, 0.70 mmol, intermediate 2), tributylphosphine (0.26 g, 1.27 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (0.32 g, 1.27 mmol), stirring at room temperature for 1 hour, decompression The residue was purified by silica gel column chromatography eluting elut elut elut elut elut elut elut -2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran Methyl 3-methyl]acetate 2B (0.13 g, yield 41.0%).

 Second step: 2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-cyclo[4.2.0]-1,3, 5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 2)

 2-[(3S)-6-[[3-[4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl] methoxy]-2 ,3-dihydrobenzo

 2-[(3S)-6-[[3-[4-methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]-1,3,5-three Ethyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid methyl ester 2B (130 mg, 0.24 mmol) dissolved in tetrahydrofuran (10 mL), methanol (10 mL) and water (20 mL), add sodium hydroxide (20 mg, 0.48 mmol), stir at room temperature for 1 hour, concentrate under reduced pressure, add 2M hydrochloric acid to pH 3, with ethyl acetate (50 mL x 2) Extraction, concentrating the organic phase, concentrating under reduced pressure, and purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 1 : 1) to give 2-[(3S)-6-[[ 3-[4-methyl-2-(3-methanesulfonylpropoxy)-5-cyclo[4.2.0]-1,3,5-triene]phenyl]methoxy]-2, 3-Dihydrobenzofuran-3-yl]acetic acid compound 2 (80 mg, yield 61.0%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.40 (t,lH), 7.32(d, 2H), 7.21(s, 1H), 7.04 (d, 1H), 6.60 (s, 1H), 6.55 - 6.45 (m , 2H), 5.04 (s, 2H), 4.75 (t, 1H), 4.33 - 4.28 (m, 1H), 4.24 (dd, 2H), 3.86 - 3.75 (m, 1H), 3.30 - 3.17 (m, 4H ), 3.10― 3.03 (m, 2H), 2.96 (s, 3H), 2.80 (dd, 1H), 2.61 (dd, 1H), 2.30 (dt, 2H), 2.22 (s, 3H).

Example 3: 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octane-1,3,5-triene]phenyl ]methoxy]-2,3- Dihydrobenzofuran-3-yl]acetic acid (compound 3)

 2-[6-[[3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-di

 First step: 1-oxy-2-bromo-benzene (3B)

 1-benzyloxy-2-bromo-benzene

The o-bromophenol 3A (60 g, 347 mmol) was dissolved in acetonitrile (300 mL), benzyl bromide (59 g, 347 mmol) and potassium carbonate (72 g, 520 mmol) were added, and the mixture was heated to reflux for 1.5 hours and then cooled. Saturated brine (200 mL) was added to the mixture, and the mixture was evaporated. 1-Benzyloxy-2-bromo-benzene 3B (91.12 g, yield 99%). Second step: 5-oxy-cyclo[4.2.0]oct-1,3,5-trien-7-one (3C)

 5-benzyloxybicyclo[4.2.0]octa-l,3,5-

1-Benzyloxy-2-bromo-benzene 3B (30.00 g, 114.07 mmol) was dissolved in tetrahydrofuran (250 mL), and 1,1-diethoxyethylene If (26.46 g, 230 mmol) and sodium amide were added. (8.97 g, 230 mmol), nitrogen-protected, heated to reflux for 34 hours, then iced water (100 g) and concentrated hydrochloric acid (30 mL) were added to the reaction mixture and stirred at room temperature for 2 hours with ethyl acetate (200 mL x 2 ). the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate _{(V / V) = 80:} l) to give a white solid 5-Benzyloxy-cyclo[4.2.0]octyl-1,3,5-trien-7-one 3C (3.2 g, yield 13%).

 The third step: 5-oxy-2-bromo-cyclo[4.2.0]octyl-1,3,5-triene-7-one (3D)

 5-benzyloxy-2-bromo-bicyclo[4.2.0] -one

00 g， 4.46 mmol)溶于冰醋酸 （60 mL) 中， 依次加入苄基三甲基三溴化铵 （2.98 g， 19.89 mmol)和氯化锌 （1.48 g， 11.15 mmol), 室 温搅拌 5小时，向反应液中加入水（40 mL)和亚硫酸钠溶液（20 mL，Na₂SO₃含量 w/w = 5%)， 用乙酸乙酯 （50 mL x 2)萃取， 合并有机相， 减压浓缩， 残留物用硅胶柱色谱分离提纯 （正己 垸 /乙酸乙酯 （v/v) = 80: 1)， 得到白色固体状的 5-苄氧基 -2-溴并环 [4.2.0]辛 -1,3,5-三烯 -7-酮 3D (0.79 g, 产率 59.0%) 。 5-benzyloxy-cyclo[4.2.0]octane-1,3,5-

00 g, 4.46 mmol) was dissolved in glacial acetic acid (60 mL), then benzyltrimethylammonium tribromide (2.98 g, 19.89 mmol) and zinc chloride (1.48 g, 11.15 mmol). Water (40 mL) and sodium sulfite solution (20 mL, Na ₂ SO ₃ content w/w = 5%) were added to the reaction mixture, and extracted with ethyl acetate (50 mL×2). The residue was purified by silica gel column chromatography (jjjjjjjjjjjjjjjjj 1,3,5-Trien-7-one 3D (0.79 g, yield 59.0%).

 Step 4: 2-Benzyloxy-5-bromo-cyclo[4.2.0]octyl-1,3,5-triene (3E)

 2-benzyloxy-5-bromo-bicyclo[4.2.0]octa-l,3,5-triene

将 5-苄氧基 -2-溴 -并环 [4.2.0]辛 -1,3,5-三烯 -7-酮 3D (0.50 g, 1.65 mmol)溶于冰醋酸 （20 mL) 中， 加入锌粉（1.07 g， 16.5 mmol), 加热至 80°C搅拌 6小时， 冷却至室温， 过滤， 将滤液减 压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 l、 =50: 1)得到白色固体状的 2- 苄氧基 -5-溴 -并环 [4.2.0]辛 -1,3,5-三烯 3E (0.22 g, 产率 47%)。

5-Benzyloxy-2-bromo-cyclo[4.2.0]oct-1,3,5-trien-7-one 3D (0.50 g, 1.65 mmol) was dissolved in EtOAc (20 mL) Zinc powder (1.07 g, 16.5 mmol) was added, and the mixture was heated to 80 ° C for 6 hours, cooled to room temperature, filtered, and the filtrate was evaporated. 50: 1) 2-Benzyloxy-5-bromo-cyclo[4.2.0]oct-1,3,5-triene 3E (0.22 g, yield 47%) was obtained as a white solid.

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.39 (m, 5H), 7.18 (d, 1H), 6.67 (d, 1H), 5.13 (s, 2H), 3.21 (m, 2H), 3.07 (m, 2H) ).

 Step 5: 3-(5-Benzyloxy-2-cyclo[4.2.0]octyl-1,3,5-triene)benzaldehyde (3F)

 3-(5-benzyloxy-2-bicyclo[4.2.0]

 2-Benzyloxy-5-bromo-cyclo[4.2.0]octyl-1,3,5-triene 3E (0.70 g, 2.42 mmol) was dissolved in toluene (15 mL), water

In a mixed solution of (15 mL) and ethanol (3 mL), 3-formylbenzeneboronic acid (0.54 g, 3.63 mmol), potassium carbonate (1.00 g, 7.26 mmol) and tetrakis(triphenylphosphine)palladium ( 0.14 g, 0.12 mmol), heated to 90. C. The reaction was stirred for 6 hr, EtOAc (EtOAc) (EtOAc) The 3-(5-benzyloxy-2-cyclo[4.2.0]oct-1,3,5-triene)-benzaldehyde 3F (0.50 g, yield 66.0%) was obtained as a yellow oil.

 Step 6: [3-(5-Benzyloxy-2-cyclo[4.2.0]octyl-1,3,5-triene)phenyl]methanol (3G)

 [3-(5-benzyloxy-2-bicyclo[ -l,3,5-trienyl)phenyl]methanol

 3-(5-Benzyloxy-2-cyclocyclo[4.2.0]oct-1,3,5-triene)-benzaldehyde 3F (0.20 g, 0.64 mmol) was dissolved in methanol (30 mL) Sodium borohydride (47 mg, 1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure to give [3-(5-oxy-2-cyclo[4.2.0]oct-1,3,5-triene. Phenyl]methanol crude product 3G, used directly in the next reaction.

 Step 7: 2-[3-(Hydroxymethyl)phenyl)-cyclo[4.2.0]octyl-1,3,5-triene]-5-ol (3H)

将 [3-(5-苄氧基 -2-并环 [4.2.0]辛 -1,3,5-三烯)苯基]甲醇粗产品 3G (200 mg， 0.63 mmol)溶于 甲醇 （10 mL) 中， 加入钯 /炭（33 mg， 钯含量 w/w = 10%)在氢气氛下， 室温反应 2小时， 过 滤， 将滤液减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙酯 （v/v) =1 : 1)得到白色 固体状的 2-[3- (羟基甲基)苯基)并环 [4.2.0]辛 -1,3,5-三烯] -5-醇 3H (0.14 g, 产率 98.0%)。 2-[3-(hydroxymethyl)phenyl]bi 5-ol

[3-(5-Benzyloxy-2-cyclocyclo[4.2.0]octyl-1,3,5-triene)phenyl]methanol crude product 3G (200 mg, 0.63 mmol) was dissolved in methanol (10) In the mL), palladium/carbon (33 mg, palladium content w/w = 10%) was added under a hydrogen atmosphere at room temperature for 2 hours, filtered, and the filtrate was concentrated under reduced pressure. /ethyl acetate (v/v) = 1 : 1) 2-[3-(hydroxymethyl)phenyl)cyclo[4.2.0]oct-1,3,5-triene] as a white solid. -5-Alcohol 3H (0.14 g, yield 98.0%).

 Step 8: [3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol (31)

 [3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

 2-[3-(Hydroxymethyl)phenyl)-cyclo[4.2.0]octyl-1,3,5-triene]-5-ol 3H (0.15 g, 0.66 mmol) was dissolved in hydrazine, hydrazine- Dimethylformamide (10 mL), 3-methylsulfonylpropyl-4-methylbenzenesulfonic acid 1C (0.11 g, 0.79 mmol) and cesium carbonate (0.25 g, 0.77 mmol), heated to 80 ° After stirring for 1 hour, the mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjj Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 31 (0.12 g, yield 52.0%).

 Step 9: 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl] Methyl methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (3J)

 Methyl 2-[6-[[3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl] methoxy] -2,3-dihydro

 [3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 31 (0.13 g, 0.37 mmol) Dissolved in dichloromethane (20 mL), followed by methyl (2,3-dihydrobenzofuran-3-yl)acetate 1H (0.094 g, 0.45 mmol), tributylphosphine (0.17 g, 0.83) Methyl) hydrazine, hydrazine-( azodicarbonyl)dipiperidine (0.21 g, 0.83 mmol), mp. , =1 : 1) 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]oct-1,3,5 as a white solid. Methyl 3-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 3J (0.13 g, yield 65.0%)

 Step 10: 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 3)

2-[6-[[3-[5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl Acetic acid 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy Methyl-2,3-dihydrobenzofuran-3-yl]acetate 3J (130 mg, 0.24 mmol) dissolved in methanol (5 mL) and water (5 mL) 48 mg, 1.21 mmol), stirring at room temperature for 2 hours, the reaction was stopped, 2M hydrochloric acid was added dropwise to pH 3, and extracted with ethyl acetate (50 mL×2). Separation and purification (dichloromethane/methanol (v/v) = 25: 1) gave 2-[6-[[3-[5-(3-methylsulfonylpropoxy)-2-cyclo[4.2. 0] Oct-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid compound 3 (80 mg, yield 64.0%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.60 (s, IH), 7.52 (d, IH), 7.41 (m, 2H), 7.31 (d, IH), 7.07 (d, IH), 6.76 (d, IH ), 6.51 (m, 2H), 5.06 (s, 2H), 4.77 (t, IH), 4.28 (dt, 3H), 3.82 (m, IH), 3.35 (dd, 4H), 3.26 (m, 2H) , 2.97 (s, 3H), 2.81 (dd, IH), 2.62 (dd, IH), 2.33 (dt, 2H).

 Example 4: 2-[(3S)-6-[[3-[4-methyl-2-((3R)-tetrahydrofuran-3-yl)-0-5-bicyclo[4.2.0] oct-1 ,3,5-three 3⁄4]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 4)

 2-[(3S)-6-[[3-[4-methyl-2-[(3R)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl ]phe nyljmethoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid

 First step: [(3S)-tetrahydrofuran-3-yl]-4-methylbenzenesulfonic acid (4B)

 [(3S)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate

(3S)-3-Hydroxy-tetrahydrofuran 4A (881.1 mg, 20 mmol) was dissolved in toluene (20 mL), and then, under nitrogen, Ν,Ν,Ν',Ν'-tetramethyl-1,6 Hexamethylenediamine (1.72 g, 10 mmol), triethylamine (1.5 g, 15 mmol), 0. C slow down A solution of p-toluenesulfonyl chloride (2.86 g, 15 mmol) in toluene (10 mL) was added dropwise, and the mixture was stirred for 2 hr. The mixture was washed with EtOAc (EtOAc) (EtOAc) 5: 1-4: 1) [(3S)-Tetrahydrofuran-3-yl]-4-methylbenzenesulfonic acid 4B (1.68 g, yield 69.0%)

 Second step: [3-[4-methyl-2-[(3R)-tetrahydrofuran-3-yl]-oxo-5-bicyclo[4.2.0]oct-1,3,5-triene]phenyl Methanol (4C)

[3-[4-methyl-2-[(3R)-tetrahydrofur -3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methanol

 [(3S)-Tetrahydrofuran-3-yl]-4-methylbenzenesulfonic acid 4B (145 mg, 0.6 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (5 mL). 3-(Hydroxymethyl)phenyl)-4-methyl-bicyclo[4.2.0]octane-1,3,5-trien-2-ol lm (120 mg, 0.5 mmol, intermediate 1) and carbonic acid Potassium (139 mg, 1.0 mmol), heated to 90 ° C for 2 hours, quenched with water (20 mL), extracted with ethyl acetate (25 mL×3), water (20 mL×3), and combined The organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjjjjjjj -methyl-2-[(3R)-tetrahydrofuran-3-yl]-oxo-5-bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 4C (155 mg, yield 99.0%).

3⁄4 NMR (400 MHz, DMSO- ₆ ): δ 7.36 (t, 1H), 7.27 - 7.21 (m, 2H), 7.17 (d, 1H), 6.60 (s, 1H), 5.20 (t, 1H), 5.05 (dt, 1H), 4.53 (d, 2H), 3.89 - 3.70 (m, 4H), 3.22 - 3.09 (m, 2H), 3.06 - 2.98 (m, 2H), 2.24 - 2.00 (m, 5H).

 The third step: 2-[(3S)-6-[[3-[4-methyl-2-((3R)-tetrahydrofuran-3-yl)-oxy-5-bicyclo[4.2.0] xin-1 ,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (4D)

 Methyl2 (3S)-6 [3-[4-methyl-2 (3R)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trie nyl]phenyl]methoxy] -2,3-dihydrobenzofuran-3-yl]acetate

[3-[4-Methyl-2-[(3R)-tetrahydrofuran-3-yl]-oxo-5-bicyclo[4.2.0]oct-1,3,5-triene]phenyl]methanol 4C (150 mg, 0.48 mmol) dissolved in dichloromethane (10 mL) and added (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 2d ( 110 mg, 0.53 mmol, intermediate 2), under the protection of nitrogen, tributylphosphine (445 mg, 1.06 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (273 mg, 1.06 mmol), After stirring at room temperature for 2 hours, it was filtered, and the filtrate was concentrated under reduced pressure to give 2-[(3S)-6-[[3-[4-methyl-2-((3R)-tetrahydrofuran-3-yl)-oxy-5- Bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid methyl ester 4D crude product (240 mg). Fourth step: 2-[(3S)-6-[[3-(4-methyl-2-[(3R)-tetrahydrofuran-3-yl]-oxo-5-bicyclo[4.2.0] octa-1 ,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 4)

 2-[(3S)-6-[[3-[4-methyl-2-[(3R)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl ]phe nyljmethoxy] -2,3-dihydrobe

 2-[(3S)-6-[[3-[4-methyl-2-((3R)-tetrahydrofuran-3-yl)-oxy-5-bicyclo[4.2.0] octyl-1,3, Methyl 5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 4D crude product (240 mg, 0.48 mmol) dissolved in methanol (3 mL) 2 mL of a mixed solution, 2M sodium hydroxide solution (1.2 mL) was added, stirred at room temperature for 2 hours, concentrated under reduced pressure, water (25 mL) was added to the reaction mixture, and 1 M diluted hydrochloric acid was added dropwise until the pH of the reaction mixture was The mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) v) = 4: 1 - Dichloromethane/methanol (v/v) = 70: 1) Obtained 2-[(3S)-6-[[3-(4-methyl-2-[ (3R)-tetrahydrofuran-3-yl]-oxo-5-bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran- 3-Based] Acetic acid compound 4 (150 mg, yield 64%).

3⁄4 NMR (400 MHz, CDC1 ₃ ): δ 7.44 - 7.38 (m, 1H), 7.33 (dd, 2H), 7.24 (s, 1H), 7.06 (d, 1H), 6.63 (s, 1H), 6.51 ( Dd, 1H), 6.47 (d, 1H), 5.06 (s, 2H), 5.02 (dd, 1H), 4.76 (t, 1H), 4.29 (dd, 1H), 4.06 - 3.88 (m, 4H), 3.81 (ddd, 1H), 3.26― 3.11 (m, 2H), 3.07 (t, 2H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.26― 2.10 (m, 5H).

 Example 5: 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2.3-b] furan- 4-yl]-oxo-4-methyl

-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 5)

 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] Oxy]-4-methyl-5-bic yclo[4 -l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

第一步： [(3aS,4R,6aR)-2,3,3a,4,5,6a-六氢呋喃 [2,3-b]呋喃 -4-基] -4-甲基苯磺酸（5B)

First step: [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuran[2,3-b]furan-4-yl]-4-methylbenzenesulfonic acid ( 5B)

 [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]-4-methylbenzenesulfonate

 (3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2,3-b]furan-4-hydroxy 5A was dissolved in dichloromethane (30 mL), added 4-Dimethylaminopiperidine (0.61 g, 5 mmol) and triethylamine (3.03 g). After stirring for 10 min, p-toluenesulfonyl chloride (2.85 g, 15 mmol) was added and allowed to react at room temperature overnight. After adding water (30 mL), EtOAc (EtOAc (EtOAc) (EtOAc) Ethyl ester (v/v) = 3: 1) [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuran[2,3-b]furan- 4-yl]-4-methylbenzenesulfonic acid 5B (2.40 g, yield 85%).

 Second step: [3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran[2,3-b]furan-4-yl]oxy] -4 -methyl-5-bicyclo[4.2.0]octane-1,3,5-triene]phenyl]methanol (5C)

[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl]oxy]-4-methyl-5-bicyclo [4.2.0] octa-l,3,5-trienyl]phenyl]methanol

 [(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2,3-b]furan-4-yl]-4-methylbenzenesulfonic acid 5B (117.22 mg , 0.41 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (5 mL), followed by 5-(3-(hydroxymethyl)phenyl; 1-4-methyl-bicyclo[4.2.0 ] octa-1,3,5-trien-2-ol lm (90 mg 0.37 mmol, intermediate 1) and potassium carbonate (102.86 mg, 0.74 mmol), heated to 90 ° C for 17 hours, water (20) The reaction mixture was diluted with EtOAc (EtOAc (EtOAc) (EtOAc) Ester (v/v) = 5: 1) [3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2,3-] b]furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 5C (120 mg, yield 92%).

3⁄4 NMR (400 MHz, DMSO- ₆ ) δ 7.36 (t, 1H), 7.25 (m, 2H), 7.17 (d, 1H), 6.60 (s, 1H), 5.77 (d, 1H), 5.20 (t, 1H), 4.89 (d, 1H), 4.53 (d, 2H), 3.99 (dt, 2H), 3.78 (m, 2H), 3.19 (m, 2H), 3.03 (m, 2H), 2.95 (m, 1H) ), 2.16 (m, 4H), 1.92 (m, 1H).

 The third step: 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2,3-b] Furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran Methyl-3-methylacetate (5D)

Methyl 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl ]oxy]-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran[2,3-b]furan-4-yl]oxy]-4-methyl -5-Bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol 5C (120 mg, 0.34 mmol) dissolved in dichloromethane (100 mL), (S) 2- (6-Hydroxy-2,3-dihydrobenzofuran-3-yl;) methyl acetate 2d (78 mg, 0.37 mm _O1 , intermediate 2), and then, under nitrogen, tributylphosphine (152) Mg, 0.75 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (189 mg, 0.75 mmol), stirred at rt overnight, filtered, EtOAc m. /ethyl acetate i N, =2: 1) 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5 ,6a-hexahydrofuran[2,3-b]furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]oct-1,3,5-triene]phenyl] Methyl oxy]-2,3-dihydrobenzofuran-3-yl]acetate 5D (110 mg, yield 60%)

 Fourth step: 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2,3-b] Furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran -3-yl]acetic acid (compound 5)

 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] Oxy]-4-methyl-5-bic yclo[4.2.0]octa-l,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid

 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran[2,3-b]furan-4 -yl]oxy]-4-methyl-5-bicyclic

[4.2.0] Methyl octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 5D (110 mg, ) soluble in methanol 2M sodium hydroxide solution (5 mL) was added to a mixture of (3 mL) and tetrahydrofuran (5 mL), and the mixture was stirred at room temperature overnight, and the mixture was evaporated. The mixture was extracted with ethyl acetate (30 mL×3). Petroleum ether / ethyl acetate i N, = 3:2) 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4 ,5,6a-hexahydrofuran[2,3-b]furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]oct-1,3,5-triene]phenyl Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid compound 5 (67 mg, yield 63%).

MS m/z (ESI): 529.5 [M+l] ⁺ .

^ NMR (400 MHz, DMSO- ₆ ) δ 12.31 (s, IH), 7.42 (t, IH), 7.35 (d, 2H), 7.26 (d, IH), 7.11 (d, IH) 6.60 (s, IH ), 6.48 (dt, 2H), 5.76 (d, IH), 5.09 (s, 2H), 4.88 (d, IH), 4.68 (t, IH), 4.19 (dd, IH), 4.00 (m, 2H) , 3.75 (m, 3H), 3.16 (m, 2H), 3.01 (m, 2H), 2.94 (m, IH), 2.69 (dd„ IH), 2.46 (d, IH), 2.16 (m, 4H), 1.90 (m, IH).

Example 6: 2-[(3S)-6-[[3-[4-methyl-2-((3S)-tetrahydrofuran-3-yl)oxy-5-cyclo[4.2.0]oct-1 ,3,5-triene]phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]methyl acetate (compound 6)

 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl ]phe nyljmethoxy] -2,3-dihydrobenzofuran-3-yl] acetic acid

First step: [PR)-Tetrahydrofuran- ³ -enyl]mesylate ( ⁶ B)

[(3R)-tetrahydrofuran-3-yl] methanesulfonate

 (3R)-Tetrahydrofuran-3-ol 6A (441 mg, 5.0 mmol) was dissolved in dichloromethane (15 mL) eluted with EtOAc. Under C, slowly add methylsulfonyl chloride (687 mg, 6.0 mmol), and add 0 after completion. After reacting for 1 hour, the reaction was quenched with water (15 mL), EtOAc (EtOAc m. Concentration gave [(3R tetrahydrofuran-3-yl]methanesulfonate 6B (825 mg, yield 99%) as pale yellow oil.

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 5.32 (ddd, 1H), 4.09 - 3.81 (m, 4H), 3.05 (s, 3H), 2.32 - 2.17 (m, 2H). Step 2: [3-[ 4-methyl-2-((3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octyl-1,3,5-trienyl]phenyl]methanol (6C)

 [3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl]phenyl]metha nol

5-(3-(Hydroxymethyl)phenyl)-4-methyl-bicyclo[4.2.0]oct-1,3,5-trien-2-ol lm (240 mg, 1.0 mmol, intermediate 1) and [(3R)-tetrahydrofuran-3-yl]methanesulfonate 6B (199 mg „ 1.2 mmol) dissolved in hydrazine, hydrazine-dimethylformamide (10 mL), replaced with nitrogen, and added with cesium carbonate (651 mg) The mixture was heated to 80 ° C, and the reaction was stirred for 30 minutes. Water (20 mL) Filtration, concentrating under reduced pressure, EtOAc (EtOAc/EtOAc) Oily [3-[4-methyl-2-((3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octyl-1,3,5-trienyl]phenyl]methanol 6C (305 mg, yield 99%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.39 (t, 1H), 7.32 - 7.27 (m, 2H), 7.23 (d, 1H), 6.63 (s, 1H), 5.06 - 4.97 (m, 1H), 4.72 (s, 2H), 4.06 - 3.85 (m, 4H), 3.19 (dd, 2H), 3.09 (t, 2H), 2.23 (s, 3H), 2.21 - 2.12 (m, 2H), 1.85 (s, 1H ).

 The third step: 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]oct-1, Methyl 3,5-trienyl]phenyl] methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (6D)

 Methyl 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3, 5- Trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

 [3-[4-Methyl-2-((3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octyl-1,3,5-trienyl]phenyl]methanol 6C (4.05 g, 13.05 mmol) was added to dichloromethane (100 mL), and methyl (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate was added 2d (2.99 g, 14.35 mmol, intermediate 2), cooled to 0 ° C under N2, then tributylphosphine (7.32 mL, 28.71 mmol) and hydrazine, Γ-(azodicarbonyl)dipiperidine (7.39 g) , 28.71 mmol), stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude product 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran- 3-yl]oxo-5-bicyclo[4.2.0]octyl-1,3,5-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate Ester 6D, used directly in the next step.

 Fourth step: 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl)oxy-5-cyclo[4.2.0]oct-1 ,3,5-triene]phenyl)methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (compound 6)

 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]octa-l,3,5-trienyl ]phenyl]methoxy] -2 ,3 -dihydrobenzofuran-3 -yl] acetic acid

2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0] sin-1,3,5 Methyl 3-trienyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 6D crude product in a mixed solution of methanol (60 mL) and tetrahydrofuran (102 mL) 2M sodium hydroxide solution (32.6 mL) was added, and the mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure. Water (30 mL) was added to the reaction mixture, and 1M diluted hydrochloric acid was added dropwise to pH 1 of the reaction mixture. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. /v) =4: 1 -Dichloromethane/methanol (v/v) = 70: 1) 2-[(3S)-6-[[3-[4-methyl] -2-[(3S)-tetrahydrofuran-3-yl)oxy-5-cyclo[4.2.0]octyl-1,3,5-triene]phenyl)methoxy]-2,3-dihydro Benzofuran-3-yl]acetic acid methyl ester compound 6 (4.7 g, total yield of 74% in the third and fourth steps).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.44 - 7.36 (m, IH), 7.36 - 7.30 (m, 2H), 7.25 (d, IH), 7.06 (d, IH), 6.63 (s, IH), 6.53 - 6.44 (m, 2H), 5.05 (d, 2H), 5.02 (ddd, IH), 4.76 (t, IH), 4.29 (dd, IH), 4.05 - 3.88 (m, 4H), 3.81 (ddd, IH ), 3.24 - 3.12 (m, 2H), 3.07 (t, 2H), 2.80 (dd, IH), 2.61 (dd, IH), 2.26 - 2.11 (m, 5H).

 MS: 485.0 [M-1]—

 Example 7; (S)-2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0] s- 1,3,5-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 7)

 (S)-2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octa-l,3,5-trien-2-yl Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

 First step: methyl 2-methoxyisonicotinate (7B)

Methyl 2-methoxyisonicotinate

 Methyl 2-chloroisonicotinate 7A (523 mg, 3 mmol) was dissolved in dioxane (5 mL), sodium methoxide (247 mg, 4.5 mmol) was added, and the mixture was stirred under nitrogen. After the system was cooled, the mixture was cooled to dryness (50 mL). EtOAc (EtOAc) Methyl 2-methoxyisonicotinate 7B (0.39 g, yield 69%) as a pale yellow liquid.

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 8.28 (d, IH), 7.40 (dd, IH), 7.31 (d, IH), 3.98 (s, 3H), 3.94 (s, 3H). Step 2: 2-Methoxypyridin-4-yl)methanol (7C)

Methyl 2-methoxyisonicotinate 7B (1.07 g, 6.4 mmol) was dissolved in tetrahydrofuran (10 mL), EtOAc (EtOAc) The system was kept at 30 ° C for 5 hours. The mixture was washed with chloroform (10 mL×2). : 1) (2-Methoxypyridin-4-yl)methanol 7C (0.8 g, yield 90%) was obtained as pale yellow liquid. 3⁄4 NMR (400 MHz, CDC1 ₃ ) 5 8.11 (t, 1H), 6.88― 6.65 (m, 2H), 4.99― 4.65 (m, 2H), 3.94 (s, 3H). Step 3: (2-A Oxypyridin-4-yl)methyl methanesulfonate (7D)

(2-methoxypyridin-4-yl)methyl methanesulfonate

 (2-Methoxypyridin-4-yl)methanol 7C (0.8 g, 5.75 mmol) was dissolved in ethyl acetate (30 mL). Triethylamine (1.12 mL, 8.05 mmol) was added with stirring, and the system was maintained at 0. Stir for 5 minutes, then slowly add methanesulfonyl chloride (0.79 g, 6.9 mmol), add the system to maintain 0 ° C for 1.5 hours, slowly add water (50 mL) to the system and quench it with ethyl acetate (50 mL) x 3) extraction, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v / v) = 1 : 1 ) (2-Methoxypyridin-4-yl)methyl methanesulfonate 7D (0.9 g, yield 72%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 8.19 (d, 1H), 6.88 (d, 1H), 6.76 (s, 1H), 5.18 (s, 2H), 3.95 (d, 3H), 3.04 (s, 3H) ).

 Fourth step: (3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octyl-1,3,5-triene-2 -yl)phenyl)methanol

(7E)

 (3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octa-l,3,5-trien-2-yl)phenyl)me thanol

(2-Methoxypyridin-4-yl)methyl methanesulfonate 7D (284 mg, 1.31 mmol) and 5-(3-(hydroxymethyl)phenyl)-4-methyl-bicyclo[4.2 .0]octyl-1,3,5-trien-2-ol lm (262 mg, 1.09 mmol, intermediate 1) dissolved in hydrazine, hydrazine-dimethylformamide (10 mL), nitrogen, Cesium carbonate (355 mg, 2.18 mmol), the system was kept at 85 ° C for 2.5 hours, the system was suction filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) =1 : 1) (3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0] sin-1,3, 5-trien-2-yl)phenyl)methanol 7E crude product (474 mg) was used directly in the next step.

 Step 5: (S)- 2-6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]oct-1 ,3,5-trien-2-benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (7F)

 (S)-methyl2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octa- l ,3, 5-trien-2-yl )benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate

 (3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]oct-1,3,5-trien-2-yl) Phenyl)methanol 7E (450 mg, 1.25 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 2d (285 mg, 1.37 mmol, intermediate 3⁄4 Dissolved in dichloromethane (10 mL), and added tributylphosphine (0.68 mL, 2.74 mmol) and hydrazine, Γ-(azodicarbonyl)dipiperidine (0.69 g, 2.74 mmol). The mixture was stirred at room temperature for 3 hours, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjj 6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]octyl-1,3,5-triene-2- Methyl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 7F (500 mg, yield 73%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 8.16 (d, 1H), 7.39 (dd, 1H), 7.36 - 7.28 (m, 2H), 7.23 (d, 1H), 7.02 (d, 1H), 6.92 (d , 1H), 6.82 (s, 1H), 6.71 (s, 1H), 6.52- 6.44 (m, 2H), 5.14 (s, 2H), 5.05 (s, 2H), 4.74 (m, 1H), 4.26 ( m, 1H), 3.95 (s, 3H), 3.79 (m, 1H), 3.71 (s, 3H), 3.19― 3.09 (m, 2H), 3.08― 2.98 (m, 2H), 2.74 (dd, 1H) , 2.55 (dd, 1H), 2.22 (d, 3H).

 Step 6: (S)-2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0] s- 1,3,5-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 7)

 (S)-2-(6-((3-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4 .0]octa- l ,3,5-trien-2-yl Benzyl)oxy)-2,3-dihydr

(S)-2-6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0] s--1,3, Methyl 5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 7F (451 mg, 0.82 mmol) dissolved in methanol (5 mL) 2 mL of a mixed solution, 2M sodium hydroxide solution (10 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure, water (25 mL) was added to the reaction mixture, and 1 M diluted hydrochloric acid was added dropwise until the pH of the reaction mixture was The organic phase is extracted with ethyl acetate (25 mL×3), dried over anhydrous sodium sulfate, filtered and evaporated. /ethyl acetate (v/v) = 3: 1) (S)-2-(6-((3-(5-; 2-methoxypyridin-4-yl)) methoxy 3-methylbicyclo[4.2.0]octyl-1,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid compound 7 (169 mg, yield 38%).

MS: 538.3 [M+1].

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 8.18 (d, IH), 7.40 (t, IH), 7.33 (d, 2H), 7.24 (d, IH), 7.05 (d, IH), 6.94 (d, IH ), 6.85 (s, IH), 6.71 (s, IH), 6.53 - 6.44 (m, 2H), 5.15 (s, 2H), 5.05 (s, 2H), 4.76 (t, IH), 4.33 - 4.17 ( m, IH), 3.97 (s, 3H), 3.81 (ddd, IH), 3.12 (d, 2H), 3.08― 2.98 (m, 2H), 2.80 (dd, IH), 2.61 (dd, IH), 2.23 (s, 3H).

Example 8: 2-(3S)-6-(( ² -fluoro-5-( ⁴ -methyl- ^2- (3-(methylsulfonyl)propoxy)-5-bicyclo[ ⁴ . ² . Octyl-1,3,5-triene)benzyloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 8)

 2-((3S)-6-((2-fhioro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trieny l)phenyl) Methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

第一步： 2-(5- (苄氧基) -3-甲基双环 [4.2.0]辛 -1,3,5-烯 -2-基) -4,4,5,5-四甲基 -1,3,2-硼酸频那醇 酯 (8B)

First step: 2-(5-(benzyloxy)-3-methylbicyclo[4.2.0]octyl-1,3,5-en-2-yl)-4,4,5,5-tetramethyl Base-1,3,2-boronic acid pinacol ester (8B)

 2-(5-(benzyloxy)-3-methylbicyclo[4.2.0]octa-l,3,5-trien-2-yl)-4,4,5,5-tetramethyl-l,3,2-dioxab orolane

将 2-苄氧基 -5-溴 -4-甲基 -双环 [4.2.0]辛 -1,3,5-三烯 li (6.06g， 20mmol)溶于乙醇 （100 mL) 中， 氮气保护下， 依次加入联硼酸频哪醇酯 （5.6 g, 19 mmol)、 [Ι,Γ-双 (；二苯基膦基)二茂铁] 二氯化钯 (1.4g, 2 mmol, PdCl₂(dppf))和乙酸钾 (5.9 g, 60 mmol), 升温至 90°C， 搅拌回流 反应 6小时。将反应体系浓缩至干， 加入水（100 mL)， 用乙酸乙酯 （100 mL)萃取， 有机相用 水（50 mL x 2)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱色谱分离提 纯 （石油醚）得到无色油状的 2-(5- (苄氧基) -3-甲基双环 [4.2.0]辛 -1,3,5-烯 -2-基) -4,4,5,5-四甲基 -1,3,2-硼酸频那醇酯 8B (4.1 g, 产率 58.6%)

2-Benzyloxy-5-bromo-4-methyl-bicyclo[4.2.0]oct-1,3,5-triene li (6.06 g, 20 mmol) was dissolved in ethanol (100 mL), nitrogen Next, boranoic acid pinacol ester (5.6 g, 19 mmol), [Ι, Γ-bis(; diphenylphosphino)ferrocene] palladium dichloride (1.4 g, 2 mmol, PdCl ₂ ( Dppf)) and potassium acetate (5.9 g, 60 mmol), warmed to 90 ° C, and stirred under reflux for 6 hours. The reaction was concentrated to dryness. EtOAc (EtOAc)EtOAc. The product was purified by silica gel column chromatography (chrome ether) to give 2-(5-(benzyloxy)-3-methylbicyclo[4.2.0]oct-1,3,5-en-2-yl as a colorless oil. -4,4,5,5-tetramethyl-1,3,2-boronic acid pinacol ester 8B (4.1 g, yield 58.6%)

 Second step: 2-fluoro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]octyl-1,3,5-triene)benzaldehyde (8C)

 2-floro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl)benzaldehyde

2-(5-(Benzyloxy)-3-methylbicyclo[4.2.0]octyl-1,3,5-en-2-yl)-4,4,5,5-tetramethyl-1 , 3,2-boronic acid pinacol ester 8B (350 mg, 1 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (5 mL), followed by 2-fluoro-5-bromobenzaldehyde (203 mg, 1 mmol), [Ι,Γ-bis(diphenylphosphino)ferrocene]palladium dichloride (37 mg, 0.05 mmol, PdCl ₂ (dppf)), potassium carbonate (276 mg, 2 mmol), warmed to The reaction was stirred at 90 ° C for 1 hour, and the reaction was completed. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated. Purification by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) .0]octyl-1,3,5-triene)benzaldehyde 8C (290 mg, yield 83.8%).

 Step 3: 2-Fluoro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]octyl-1,3,5-triene)benzyl alcohol (8D)

 2-floro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl) phenylmethanol

 Dissolving 2-fluoro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]oct-1,3,5-triene)benzaldehyde 8C (290 mg, 0.84 mmol) Methanol (10 mL), cooled to 0 ° C, slowly added sodium borohydride (37.83 mg, 1 mmol), and stirred at 0 ° C for 0.5 h. The reaction mixture was concentrated under reduced pressure. Ether/ethyl acetate (v/v) = 3: 1) to give 2-fluoro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]oct-1 as a colorless oil. 3,5-Triene)benzyl alcohol 8D (210 mg, yield 72%).

 Step 4: 2-Fluoro-4-(5-hydroxy-3-methyl-2-bicyclo[4.2.0]octyl-1,3,5-triene)benzyl alcohol (8E)

2-floro-4-(5-hydroxy-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl) phenylmethanol

 Dissolving 2-fluoro-4-(5-benzyloxy-3-methyl-2-bicyclo[4.2.0]oct-1,3,5-triene)benzyl alcohol 8D (210 mg, 0.6 mmol) Palladium carbon (21 mg, palladium content w/w = 10%) and potassium carbonate (21 mg) were successively added to methanol (5 mL), and hydrogen was replaced three times, and reacted at 30 ° C for 2 hours. The reaction mixture was concentrated to dryness EtOAc (EtOAc m. 3-Methyl-2-bicyclo[4.2.0]octane-1,3,5-triene)benzyl alcohol 8E (140 mg, yield 90%).

 Step 5: 2-Fluoro-4-(5-(3-methanesulfonylpropoxy)-5-3-methyl-2-bicyclo[4.2.0]oct-1,3,5-triene) Benzyl alcohol (8F)

2-floro-4-(5-(3-methylsulfonylpropoxy)-3-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl) phenylmethanol

 2-Fluoro-4-(5-hydroxy-3-methyl-2-bicyclo[4.2.0]oct-1,3,5-triene)benzyl alcohol 8E (140 mg, 0.54 mmol) was dissolved in hydrazine. To a solution of 3-methylsulfonylpropyl-4-methylbenzenesulfonic acid 1C (158 mg, 0.54 mmol) and cesium carbonate (352 mg, 1.08 mmol) in hydrazine-dimethylformamide (2 mL). Heat to 90 ° C and react for 2 hours. The reaction solution was cooled to room temperature, EtOAc (EtOAc)EtOAc. The product was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) -3-Methyl-2-bicyclo[4.2.0]oct-1,3,5-triene)benzyl alcohol 8F (190 mg, yield 93%).

 Step 6: 2-(3S)-6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy))-5-bicyclo[4.2.0] s- Methyl 1,3,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate (8G)

 Methyl2-((3S)-6-((2-fluoro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-tr ienyl)phenyl) )methoxy)-2 3-dihydrobenzofuran-3-yl)acetate

2-Fluoro-4-(5-(3-methanesulfonylpropoxy)-5-3-methyl-2-bicyclo[4.2.0]oct-1,3,5-triene)benzyl alcohol 8F (190 mg, 0.5 mmol) dissolved in dichloromethane (5 mL), followed by the addition of methyl (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 2d (104 mg, 0.5 mmol) and azobiscarbonyldipiperidine (251 mg, 1 mmol), cooled to 0. C, slowly drip into the three Base phosphine C202 mg, 1 mmol), the reaction was kept at 0 ° C for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v / v) = 1 : 1) 2-(3S)-6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy))-5-bicyclo[4.2.0] octyl) as a white solid Methyl-1,3,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 8G (210 mg, yield 76%).

 Step 7: 2-(3S)-6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy))-5-bicyclo[4.2.0] s- 1,3,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 8)

 2-((3S)-6-((2-fluoro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trieny l)phenyl) Methoxy)-2,3-dih drobenzofuran-3-yl)acetic acid

 2-(3S)-6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy)-5-bicyclo[4.2.0]oct-1,3) ,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 8G (210 mg, 0.37 mmol) suspended in methanol (10 mL) A solution of sodium hydroxide (300 mg, 7.58 mmol) in water (1 mL) was added and the mixture was stirred at room temperature for 4 hours. The reaction system was concentrated under reduced pressure, water (10 mL) was added, and the mixture was adjusted to pH 3 with 2M diluted hydrochloric acid, extracted with dichloromethane (20 mL x 2), and the organic phase was combined with water (10 mL x 2 Washed, dried over anhydrous sodium sulfate (2 g), EtOAc (EtOAc m. 6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene)benzene (Methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid compound 8 (140 mg, yield 68%).

MS: 554.7 [M+1] ⁺ .

3⁄4 NMR (400 MHz, CDC1 ₃ ) 57.36 (m, lH), 7.18 (m, lH), 7.05 (m, 2H), 6.60 (s, lH), 6.47 (m, 2H), 5.13 (s, 2H) , 4.75(t,lH), 4.22(m,3H), 3.78(m,lH), 3.19(m,4H), 3.01(m,2H), 2.96(s,3H), 2.77(dd,lH), 2.58 (dd, lH), 2.29 (m, 2H), 2.17 (s, 3H).

 Example 9: 2-[(3S)-6-[[3-(2-Benzyloxy-4-methyl-cyclo[4.2.0]oct-1,3,5-triene)phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 9)

 2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methoxy]-2,3-di Hydrobenzofuran-3-yl] acetic acid

 First step: 2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-cyclo[4.2.0]oct-1,3,5-triene)benzene Methyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (9B)

Methyl2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methoxy]- 2 ,3 -dihydrobenzofuran -3 -yl] acetate

 3-(5-Benzyloxy)-2-cyclo[4.2.0]octyl-1,3,5-triene)phenyl)methanol 3G (0.62 g, 1.88 mmol) was dissolved in dichloromethane. (10) 2-(6-Hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 2d (411 mg, 1.97 mmol, intermediate 2), under nitrogen Tributylphosphine (838 mg, 4.14 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (1.04 g, 4.14 mmol), EtOAc. Purification by chromatography (petroleum ether / ethyl acetate (v/v) = 5: 1) to give 2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-) as a white solid. 5-cyclo[4.2.0]octyl-1,3,5-triene)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 9B (1.0 g, Yield 100%).

 Second step: 2-[(3S)-6-[[3-(2-Benzyloxy-4-methyl-cyclo[4.2.0]oct-1,3,5-triene)phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 9)

2-[(3S)-6-[[3-(2-benzyloxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenyl]methoxy]-2,3-dihydr Obenzofuran-3 -yl] acetic acid

将 2-[(3S)-6-[[3-(2-苄氧基 -4-甲基 -5-并环 [4.2.0]辛 -1,3,5-三烯)苯基]甲氧基 ]-2,3-二氢苯并呋 喃 -3-基]乙酸甲酯 9B (1.0 g, 1.88 mmol)溶于甲醇（5 mL)和四氢呋喃 （5 mL) 的混合溶液中， 加入 2M的氢氧化钠溶液（5 mL)，室温搅拌过夜，停止反应，减压浓缩，向残留物中加入水（25 mL), 滴加 1M稀盐酸至反应液 pH≤2， 用乙酸乙酯（30 mL x 3)萃取， 合并有机相并用无水硫 酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离提纯（石油醚 /乙酸乙酯 （v/v) = 3:2) 得到白色固体状的 2-[(3S)-6-[[3-(2-苄氧基 -4-甲基 -并环 [4.2.0]辛 -1,3,5-三烯)苯基]甲氧基 ]-2,3-二 氢苯并呋喃 -3-基]乙酸化合物 9 (400 mg， 产率 45%)。

2-[(3S)-6-[[3-(2-Benzyloxy-4-methyl-5-cyclo[4.2.0]octyl-1,3,5-triene)phenyl]- Methyl oxy]-2,3-dihydrobenzofuran-3-yl]acetate 9B (1.0 g, 1.88 mmol) was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL). Sodium hydroxide solution (5 mL), stirring at room temperature overnight, the reaction was stopped, concentrated under reduced pressure, water (25 mL) was added to the residue, 1M diluted hydrochloric acid was added dropwise to pH ≤ 2, with ethyl acetate (30 mL) x 3) Extraction, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v / v) = 3:2) 2-[(3S)-6-[[3-(2-Benzyloxy-4-methyl-cyclo[4.2.0] oct-1,3,5-triene)phenyl]) as a solid Oxy]-2,3-dihydrobenzofuran-3-yl]acetic acid compound 9 (400 mg, yield 45%).

3⁄4 NMR (400 MHz, DMSO- ₆ ) δ 12.31 (s, 1H), 7.44-7.33 (m, 8H), 7.25 (d, 1H), 7.11 (d, 1H), 6.71 (s, 1H), 6.49- 6.46 (m, 2H), 5.19 (s, 2H), 5.09 (s, 2H) 4.68 (t, 1H), 4.19-4.17 (m, 1H), 3.69-3.66 (m, 1H), 3.17 (m, 2H) ), 2.98 (m, 2H), 2.69 (dd, 1H), 2.46 (dd, 1H), 2.17 (s, 3H).

 Example 10: 2-[(3S)-6-[[3-(2-(4-hydroxytetrahydrofuran-3-yl)oxy)-4-methyl-5-cyclo[4.2.0]oct-1 ,3,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 10)

 2-[(3S)-6-[[3-[2-(4-hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trieny l] Phenyl]methoxy] -2,3 -dihydrobenzofuran-3 -yl] acetic acid

第一步 :3-(2-羟基 -4-甲基 5-双环 [ 4.2.0 ]辛-1,3,5-三烯) -苯甲醛（10A)

First step: 3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]oct-1,3,5-triene)-benzaldehyde (10A)

 3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl)benzaldehyde

 5-Bromo-4-methyl-bicyclo[4.2.0]oct-1,3,5-trien-2-ol 3e (32.6 g, 0.15 mol, intermediate 3) and 3-formylbenzeneboronic acid ( 27.53 g, 0.18 mol) dissolved in toluene (500 mL), added 2M potassium carbonate solution (460 mL), and added ethanol.

(200 mL), tetratriphenylphosphine palladium (14.14 g, 12.2 mmol), 90 was added under a nitrogen atmosphere. The reaction was carried out for 18 hours at C. Reaction After cooling to room temperature, ethyl acetate (500 mL) was added, and the mixture was washed with water (100 mL×2). Petroleum ether / ethyl acetate i N, = 6 / 1) to give 3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0] oct-1,3,5-triene) as a yellow solid. - benzaldehyde 10A (30.0 g, yield 82.4%).

 Step 2: 3-(2-(4-Hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)benzaldehyde (10B)

3-[2-(4-hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octa-l,3,5-trienyl]benzaldehyde

将 3-(2-羟基 -4-甲基 5-双环 [ 4.2.0]辛 -1,3,5-三烯) -苯甲醛 10A (714.8 mg, 3.0 mmol)、 3,4-环 氧四氢呋喃 （1.9 g， 22.5 mmol)和碳酸钾 （622 mg， 4.5 mmol) 依次加入到乙醇 （10 mL) 中， 在 100°C微波反应 75分钟。向反应体系中加入乙酸乙酯 （50 mL)，用饱和食盐水（10mL x 2)洗 涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱色谱分离提纯 （石油醚 /乙酸乙 酯 （v/v) =1/1) 得到淡黄色油状的 3-(2-(4-羟基四氢呋喃 -3-基)氧 -4-甲基 -5-双环 [4.2.0]辛 -1,3,5- 三烯)苯甲醛 10B (897 mg, 产率 100%)。

3-(2-Hydroxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-benzaldehyde 10A (714.8 mg, 3.0 mmol), 3,4-epoxytetrahydrofuran (1.9 g, 22.5 mmol) and potassium carbonate (622 mg, 4.5 mmol) were sequentially added to ethanol (10 mL) and reacted at 100 ° C for 75 minutes. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with EtOAc EtOAc. Ethyl acetate (v/v) = 1/1) afforded 3-(2-(4-hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4. 1,3,5-triene)benzaldehyde 10B (897 mg, yield 100%).

3⁄4 NMR (400 MHz, DMSO- ₆ ) δ 10.06 (s, 1H), 7.84 (dd, 2H), 7.73 - 7.60 (m, 2H), 6.68 (s, 1H) _: 5.42 (d, 1H), 4.73 ( d, 1H), 4.24 (t, 1H), 3.97 (ddd, 2H), 3.66 - 3.50 (m, 2H), 3.28 - 3.11 (m, 2H), 3.06 (t, 2H), 2.21 (s, 3H) .

 Third step: [4-[[5-(3-formylphenyl)-4-methyl-2-cyclo[4.2.0]octyl-1,3,5-triene]oxy]-tetrahydrofuran- 3-based]acetate (10C)

 [4-[[5-(3-formylphenyl)-4-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl]oxy]tetrahydrofuran-3-yl] acetate

3-(2-(4-Hydroxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]oct-1,3,5-triene)benzaldehyde 10B (1.02 g, 3.15 Methyl acetate (600 mg) and triethylamine (1.4 g) were added to dichloromethane (20 ml) and reacted for 1 hour under nitrogen. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, Purification by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) Bicyclo[4.2.0]octane-1,3,5-triene]oxy]-tetrahydrofuran-3-yl]acetate 10C (600 mg, yield 54%). Fourth step: [4-[[5-[3-(hydroxymethyl)phenyl]-4-methyl-2-cyclo[4.2.0]octyl-1,3,5-triene]oxy] Tetrahydrofuran-3-yl]acetate (10D)

 [4-[[5-[3-(hydroxymethyl)phenyl]-4-methyl-2-bicyclo[4.2.0]octa-l,3,5-trienyl]oxy]tetrahydrofu ran-3-yl] acetate

 [4-[[5-(3-Formylphenyl)-4-methyl 2-bicyclo[4.2.0]octyl-1,3,5-triene]oxy]-tetrahydrofuran-3-yl]B The ester 10C (600 mg, 1.64 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (10 mL), cooled to 0 ° C, and sodium borohydride (124 mg, 3.27 mmol) was added. minute. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) Concentration under reduced pressure, the residue was purified by silica gel column chromatography eluting eluting eluting eluting 4-methyl-2-cyclo[4.2.0]octyl-1,3,5-triene]oxy]tetrahydrofuran-3-yl]acetate 10D (350 mg, yield 60%).

^ NMR (400 MHz, DMSO- ₆ ) δ 7.36 (t, IH), 7.25 (d, 2H), 7.17 (d, IH), 6.68 (s, IH), 5.17 (dd, 2H), 4.95 (d, IH), 4.53 (d, 2H), 4.06 (ddd, 2H), 3.91 - 3.71 (m, 2H), 3.18 - 3.05 (m, 2H), 3.02 (t, 2H), 2.18 (s, 3H), 2.09 (s, 3H).

 Step 5: 2-[(3S)-6-[[3-[2-(4-Acetoxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]oct-1 ,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (10E)

 Methyl2-[(3S)-6-[[3-[2-(4-acetoxytetmhydrofiimn-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]octa- 1,3,5 rienyl]phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetate

[4-[[5-[3-(Hydroxymethyl)phenyl]-4-methyl-2-cyclo[4.2.0]octyl-1,3,5-triene]oxy]tetrahydrofuran-3 -Acetyl acetate 10D (340 mg, 0.932 mmol) was added to dichloromethane (15 mL) and (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl was added. Methyl acetate 2d (202 mg, 0.969 mmol, intermediate 2), cooled to zero under nitrogen. C, Tributylphosphine (0.51 mL, 2.03 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (512 mg, 2.03 mmol) were added sequentially and stirred at room temperature for 3 hr. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 2-[(3S)-6-[[3-[2-(4-acetoxytetrahydrofuran-3-yl;)oxy-4-methyl-5-bicyclo[ 4.2.0] octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 10E crude product, directly used in the next step Reaction.

 Step 6: 2-((S)-6-((3-(5-((3,4-S,S/R,R)-hydroxytetrahydrofuran-3-yl)oxy)-3-methyl Bicyclo[4.2.0]octyl-1,3,5-trien-2-yl)phenyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 10)

 2-((S)-6-((3-(5-((3,4-S,S/R,R)-4-hydroxytetrahydrofuran-3-yl)oxy)-3-methylbicyclo[4.2.0 ]octa ■l,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

 2-[(3S)-6-[[3-[2-(4-Acetoxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]oct-1,3, Methyl 5-triene]phenyl] methoxy]-2,3-dihydrobenzofuran-3-yl]acetate 10E The crude product was dissolved in a mixture of methanol (5 mL) and tetrahydrofuran (10 mL) 2M sodium hydroxide solution (2.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. Water (1 mL) was evaporated. Drying, filtration, and concentrating the filtrate under reduced pressure. EtOAc m. 2-((S)-6-((3-(5-((3)4-S,S/R,R)-hydroxytetrahydrofuran-3-yl)oxy)-3-methyl) Bicyclo[4.2.0]octyl-1,3,5-trien-2-yl)phenyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid compound 10 (330 mg, fourth The total yield of step and step 5 is 71%).

3⁄4 NMR (400 MHz, DMSO- ₆ ) δ 12.31 (s, IH), 7.42 (t, IH), 7.37 - 7.31 (m, 2H), 7.26 (d, IH),

7.11 (d, IH), 6.63 (s, IH), 6.48 (dt, 2H), 5.40 (d, IH), 5.09 (s, 2H), 4.75 - 4.64 (m, 2H), 4.29 - 4.14 (m, 2H), 4.05 (d, IH), 3.90 (dd, IH), 3.78 (d, IH), 3.73 - 3.64 (m, IH), 3.61 (dd, IH), 3.26 - 3.07 (m, 2H), 3.01 (t, 2H), 2.69 (dd, IH), 2.46 (d, IH), 2.17 (s, 3H).

 MS: 501.1 [M-1] - Example 11: 2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-bicyclo[ 4.2.0] 辛-1(6),2,4-triene)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 11)

 2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phenyl] Methoxyl]-2,3-dihydrobenzofuran-3- l]acetic acid

 First step 2-cyclopropoxyethanol (11B)

2-cyclopropoxyethanol

The magnesium powder (8.9 g, 0.36 mol) was mixed with the catalytic amount of elemental iodine, and a solution of dibromoethane (46 g, 0.24 mol) in tetrahydrofuran (200 mL) was added to the mixture under nitrogen atmosphere at 40-55 °C. . A solution of 2-(2-bromoethyl)-1,3-dioxolan 11A (10 g, 0.056 mol) in tetrahydrofuran (75 mL) was added to the reaction and the mixture was reacted at 45 ° C for 16 hours. The reaction was quenched with aqueous EtOAc (EtOAc) (EtOAc (EtOAc) The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / _V a; »= 10: 1) to give a pale yellow oil of 2-cyclopropyl-ethoxyethanol 11B (1.08 g, 19% yield).

 Second step: 2-cyclopropyloxyethyl 4-methylbenzenesulfonate (11C)

2-cyclopropoxyethyl 4-methylbenzenesulfonate

2-Cyclopropyloxyethanol 11B (500 mg, 4.9 mmol) was added to a mixed solution of sodium hydroxide (588 mg, 14.7 mmol) in water (4 mL) and tetrahydrofuran (7 mL) and cooled to 0 ° C, A solution of toluenesulfonyl chloride (1 g, 5.4 mmol) in tetrahydrofuran (4 mL) was added dropwise to the mixture, and the mixture was reacted at 0 ° C for 6 hr. The organic phase was washed with a saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. v) = 30: 1) 2-cyclopropyloxyethyl group as a colorless oil

4-methylbenzenesulfonate llC (540 mg, yield 43%).

 The third step: 3-[2[2-(cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzene Formaldehyde (11D) 3-[2[2-(cyclopropoxy)ethylox -4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]benzaldehyde

 Dissolve 2-cyclopropyloxyethyl-4-methylbenzenesulfonate 11C (600 mg, 2.52 mmol) in hydrazine, hydrazine-dimethylformamide (15 mL) and add 3- (2-Hydroxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-benzaldehyde 10A (680 mg 2.52 mmol) and cesium carbonate (12.50 g, 7.56 mmol), heated The reaction mixture was stirred at 90 ° C for 17 hours, and the mixture was diluted with water (50 mL). Purification by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) 5-5-bicyclo[4.2.0]oct-1(6), 2,4-triene)benzaldehyde 11D (620 mg, yield 76%).

 Fourth step: 3-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene] Benzyl alcohol (11E) 3-[2[2-(cyclopropoxy)ethyloxy]-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]

Phenyl] methanol

 3-[2[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzaldehyde 11D ( 520 mg, 1.61 mmol) dissolved in MeOH (5 mL) EtOAc (EtOAc) 3) Extraction, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 10:1) Oily 3-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene]benzyl alcohol 11E (520 mg, yield 98%).

 Step 5: 2-[(3S)-6-[[3-[2-[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1 (6), 2,4-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (11F)

Methyl-2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethyloxy]-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4- Trie nyl]phenyl]methoxyl]-2,3-dihydrobenzofuran-3-yl] acetate

 3-[2[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1(6), 2,4-triene]benzyl alcohol 11E ( 470 mg, 1.45 mmol) was dissolved in dichloromethane (7 mL), and methyl (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 2d (304) Mg, 1.52 mmol, Intermediate 2), under the protection of nitrogen, tributylphosphine (645 mg, 3.19 mmol) and hydrazine, hydrazine-(; azodicarbonyl)dipiperidine (805 mg, 3.19 mmol), After stirring at room temperature, the mixture was filtered, and then evaporated tolululululujjjjjjjjjjjjjjjjjjjjjjjjjj 3-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene]phenyl]- Methyl oxy]-2,3-dihydrobenzofuran-3-yl]acetate 11F (630 mg, yield 82%).

Step 6: 2-[(3S)-6-[[3-[2-[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1 (6), 2,4-triene]phenyl]methoxy]- ² ,3-dihydrobenzofuran-3-yl]acetic acid (Compound 11)

 2-[(3S)-6-[[3-[2-[2-(cyclopropoxy)ethyloxy]-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl] Phe nyljmethoxyl] -2,3 -di

 2-[(3S)-6-[[3-[2-[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0] oct-1(6) ,2,4-Triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 11F (300 mg, 0.70 mmol) dissolved in methanol (5 mL) and tetrahydrofuran (5 mL) of a mixed solution, 2M sodium hydroxide solution (5 mL) was added, stirred at room temperature overnight, the reaction was stopped, concentrated under reduced pressure, water (25 mL) was added to the residue, and 1 M diluted hydrochloric acid was added dropwise. The mixture was extracted with ethyl acetate (30 mL×3). (v/v) = 2: 1) 2-[(3S)-6-[[3-[2-[2-[2-(cyclopropoxy)ethoxy]-4-methyl-) 5-bicyclo[4.2.0]oct-1(6),2,4-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid compound 11 (400 mg , yield 77%).

3⁄4 NMR (400 MHz, DMSO- ₆ ) δ 12.32 (s, IH), 7.41 (t, 1 H), 7.35-7.33 (m, 2H), 7.25 (d, IH), 7.11 (d, IH), 6.61 (s, IH), 6.48-6.46 (m, 2H), 5.09 (s, 2H), 4.68 (t, IH), 4.21-4.17 (m, 3H), 3.74-3.64 (m, 3H), 3.38-3.33 (m, IH), 3.17 (td, 2H), 2.99 (td, 2H), 2.69 (dd, IH), 2.47 (dd, IH), 2.16 (s, 3H), 0.52-0.48 (m, 2 H) , 0.46-0.43 (m, 2H).

Example 12: 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-bicyclo[4.2.0]oct-1(6), 2,4-tris)phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 12) 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phenyl]methoxyl]-2, 3- dihydrobenzofuran-3-yl] acetic acid

第一步： 3-[2- [叔丁基 (二甲基)硅]氧 -4-甲基 -5-双环 [4.2.0]辛 -1(6),2,4-三烯)苯甲醛 (12B) 3-[2[ter^butyl(dimethyl)silyl]ox -4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]benzadehyde

First step: 3-[2-[tert-butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzene Formaldehyde (12B) 3-[2[ter^butyl(dimethyl)silyl]ox -4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]benzadehyde

 3-(2-Hydroxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-benzaldehyde 10A (0.50 g, 2.1 mmol), tert-butyldimethyl chloride Silane (0.63 mg, 4.2 mmol) was dissolved in tetrahydrofuran (5 mL), and imidazole (0.43 mg, 6.3 mmol) was added at room temperature for 30 min. The reaction was quenched with water (10 mL). The organic phase was combined and dried over anhydrous sodium sulfate. EtOAc was evaporated. [2 [tert-Butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzaldehyde 12B (0.60 g, produced Rate 81%).

 Second step: 3-[2-[tert-butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene]benzene Methanol (12C)

[3-[2[tert-bu1yl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4 rienyl]phenyl]metha nol

 3-[2-[tert-Butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzaldehyde 12B ( 0.6 g, 1.70 mmol) dissolved in MeOH (5 mL) EtOAc (EtOAc) (EtOAc) 3) Extraction, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v / v) = 20: 1) Oily 3-[2[tert-butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]octyl-1(6),2,4-triene)benzyl alcohol 12C (0.6 g, yield 98%).

 The third step: 2-[(3S)-6-[[3-[2-tert-butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1 (6 , 2,4-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (12D)

 Methyl-2-[(3S)-6-[[3-[2-teW-butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4 -tri enyl]phenyl]methoxyl]-2,3-dihydrobenzofuran-3-yl]acetate

 3-[2[tert-Butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzyl alcohol 12C (600 Methyl, 1.70 mmol) is dissolved in dichloromethane (7 mL), and methyl (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 2d (374 mg) 1.80 mmol, intermediate 2), under nitrogen, add tributylphosphine (756 mg, 3.74 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (943 mg, 3.74 mmol), stir at room temperature After the overnight filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjj [3-[2-tert-Butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene]phenyl]methoxy Methyl-2,3-dihydrobenzofuran-3-yl]acetate 12D (573 mg, yield 57%).

 Fourth step: 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)benzene Methyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (12E)

 Methyl-2 (3S)-6 [3-(hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl)phenyl]methoxyl ] -2,3-dihydrobenzofuran- 3 -yl] acetate

将 2-[(3S)-6-[[3-[2-叔丁基 (二甲基)硅]氧 -4-甲基 -5-双环 [4.2.0]辛 -1(6),2,4-三烯] 苯基]甲氧 基] -2,3-二氢苯并呋喃 -3-基]乙酸甲酯 12D (470 mg, 0.86 mmol), 四丁基氟化铵 (818 mg, 2.6 mmol),溶于四氢呋喃 （8 mL), 室温搅拌 30分钟后加水（50 mL) 淬灭反应，用乙酸乙酯 （30 mL x 3)萃取， 合并有机相并用无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱色谱分 离提纯 （石油醚 /乙酸乙酯 （_V/v) = 10_: l)得到无色粘稠状液体 2-[(3S)-6-[[3-(2-羟基 -4-甲基 -5-双 环 [4.2.0]辛 -1(6),2,4-三烯)苯基]甲氧基 ]-2,3-二氢苯并呋喃 -3-基]乙酸甲酯 12E (300 mg, 产率 81%)。

2-[(3S)-6-[[3-[2-tert-Butyl(dimethyl)silyl]oxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2 ,4-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester 12D (470 mg, 0.86 mmol), tetrabutylammonium fluoride (818 mg, 2.6 mmol), dissolved in tetrahydrofuran (8 mL), EtOAc (EtOAc) the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate _{(V / v) = 10:} l) to give a colorless viscous liquid 2 - [(3S) -6 - [[3 -(2-hydroxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)phenyl]methoxy]-2,3-dihydrobenzofuran Methyl 3-methyl]acetate 12E (300 mg, yield 81%).

 Step 5: 2-[(3S)-6-[[3-(2-Hydroxy-4-methyl-bicyclo[4.2.0]oct-1(6),2,4-triene)phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 12)

2-[(3S)-6-[[3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phenyl]methoxyl]-2, 3-

 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]oct-1(6),2,4-triene)phenyl]- Methyl oxy]-2,3-dihydrobenzofuran-3-yl]acetate 12E (300 mg, 0.70 mmol) was dissolved in a mixture of methanol (3 mL) and tetrahydrofuran (3 mL). Sodium hydroxide solution (5 mL), stirring at room temperature overnight, quenched, concentrated under reduced pressure, water (25 mL), and 1M diluted hydrochloric acid was added dropwise to pH ≤2, with ethyl acetate (30 mL) x 3) Extraction, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and the residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v / v) = 2: l) Solid 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-bicyclo[4.2.0]oct-1(6),2,4-triene)phenyl]- Oxy]-2,3-dihydrobenzofuran-3-yl]acetic acid compound 12 (280 mg, yield 90%).

3⁄4 NMR (400 MHz, DMSO- ₆ ) δ 12.30 (s, IH), 9.33 (s, IH), 7.39 (t, IH), 7.32-7.30 (m, 2H),

7.23 (d, IH), 7.10 (d, IH), 6.50-6.45 (m, 3H), 5.08 (s, 2H), 4.68 (t, IH), 4.19 (dd, IH), 3.71-3.68 (m, IH), 2.93 (s, 4H), 2.69 (dd, IH), 2.47 (dd, IH), 2.14 (s, 3 H).

 Example 13: (S)-2-(6-((2-Chloro-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo)[4.2.0] s-l (6), 2,4-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 13)

 (S)-2-(6-((2-chloro-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l(6),2,4-trien -2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

 First step: 5-bromo-4-methyl-2-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octyl-1,3,5-triene (13A)

 5-bromo-4-methyl-2-(3-methylsulfonylpropoxy)bicyclo[4.2.0]octa-1 ,5-triene

 5-Bromo-4-methyl-bicyclo[4.2.0]oct-1,3,5-trien-2-ol 3e (2.13 g, 10 mmol, intermediate 3) was dissolved in hydrazine, hydrazine-dimethyl In the formamide (2 mL), 3-methylsulfonylpropyl-4-methylbenzenesulfonic acid 1C (2.91 g, 10 mmol) and cesium carbonate (6.5 g, 90 ° C, were reacted for 4 hours). /o

 , 20 mmol), heating until the reaction solution was cooled to room temperature, water (100 mL) was added, extracted with ethyl acetate (100 mL×1), and the organic layer was washed with water (50 mL×2), anhydrous magnesium sulfate (5 g Drying, filtration, and concentrating the filtrate under reduced pressure. EtOAc m. (3-(Methanesulfonyl)propoxy)bicyclo[4.2.0]oct-1,3,5-triene 13A (1.67 g, yield 50%). Second step: 4,4,5,5-tetramethyl-2-(3-methyl-5-(3-(methylsulfonyl)propoxy)-2-bicyclo[4.2.0]oct-1 ,3,5-triene)-1,3,2-boronic acid pinacol ester (13B)

 4,4,5,5-tetramethyl-2-(3-methyl-5-(3-methylsulfonylpropoxy)-2-bicyclo[4.2.0]octa-l,3,5-trienyl)-l ,3 ,2- Dioxaborolane

5-Bromo-4-methyl-2-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]oct-1,3,5-triene 13A (1.67 g, 5 mmol) was dissolved in ethanol (200 mL), under the protection of nitrogen, boranoic acid pinacol ester (1.27 g, 5 mmol), [Ι, Γ-bis(; diphenylphosphino)ferrocene] palladium dichloride (146) Mg, 0.04 mmol, PdC12 (dppf)) and potassium acetate (1.5 g, 15 mmol), warmed to 90 ° C, stirred and refluxed for 2 hours. The reaction was concentrated to dryness and water (50 mL). The mixture was extracted with ethyl acetate (50 mL×1), EtOAc (EtOAc) Petroleum ether / ethyl acetate (v / v) = 5: 1) 4,4,5,5-tetramethyl-2-P-methyl-5-(3-(methylsulfonyl) as a colorless oil Propoxy)-2-bicyclo[4.2.0]octane-1,3,5-triene)-1,3,2-boronic acid pinacol ester 13B (1.78 g, yield 94%). The third step: 2-chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene) Benzaldehyde (13C) 2-chloro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl)benzaldeh yde

4,4,5,5-tetramethyl-2-(3-methyl-5-(3-(methylsulfonyl)propoxy)-2-bicyclo[4.2.0]oct-1,3, 5-triene) -1,3,2-boronic acid pinacol ester 13B (1.78 mg, 4.68 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (20 mL), followed by 2-chloro-5- Bromobenzaldehyde (1.03 g, 4.68 mmol), [Ι, Γ-bis(diphenylphosphino)ferrocene]palladium dichloride (171 mg, 0.234 mmol, PdCl ₂ (dppf)) and potassium carbonate (1.29) g, 9.36 mmol), the temperature was raised to 90 ° C, and the reaction was stirred for 2 hours, and the reaction was completed. Water (100 mL) was added to the reaction mixture, which was extracted with ethyl acetate (100 mL×1). The organic phase was washed with water (50 mL×2), dried over anhydrous sodium sulfate (5 g), filtered, concentrated and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate _{(V / V) = 3:} l) to give colorless oil of 2-chloro-5- (4-methyl-2- (3- ( Methanesulfonyl)propoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene)benzaldehyde 13C (570 mg, yield 31%).

 Fourth step: 2-chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0]octyl-1,3,5-triene) Benzyl alcohol (13D) 2-chloro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo[4.2.0]octa-l,3,5-trienyl)phenylme thanol

 2-Chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene)benzaldehyde 13C (393 mg, 1 mmol) dissolved in methanol (10 mL), cooled to 0 ° C, slowly added sodium borohydride (37.83 mg, 1 mmol), and kept at 0 ° C for 0.5 hour. The reaction mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate i N) = 1 : 1) 2-chloro-5-(4-methyl-2-(3-(methylsulfonyl)) Propoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene)benzyl alcohol 13D (310 mg, yield 78.4%).

 Step 5: 2-(3S)-6-((2-Chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0] octyl Methyl-1,3,5-triene)benzyloxy)-2,3-dihydrobenzofuran-3-yl)acetate (13E)

Methyl 2-((3S)-6-((2-chloro-5-(4-methyl-2-(3-methylsulfonylpropoxy)-5-bicyclo [4.2.0] octa-l,3,5-trienyl)phenyl )methoxy)-2,3-dihydrobenzofuran-3-yl)acetate

2-Chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene)benzyl alcohol 13D (300 mg, 0.76 mmol) dissolved in dichloromethane (5 mL), followed by (S)-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl;) methyl acetate 2d (158 mg, 0.76 mmol) and azodicarbonyldipiperidine (382 mg, 1.52 mmol), cooled to 0 ° C, slowly dropwise dropwise tributylphosphine (307 mg, 1.52 mmol). The reaction was carried out for 0.5 hours, and the reaction mixture was evaporated to dryness mjjjjjjjjjjjjjjjjjjjjj (2-Chloro-5-(4-methyl- _2- (3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0]oct-1,3,5-triene) benzyloxy Methyl 2,3-dihydrobenzofuran-3-yl)acetate 13E (340 mg, yield 79%).

 Step 6: (S)-2-(6-((2-Chloro-5-(3-methyl-5-(3-(methylsulfonyl))propoxy)bicyclo[4.2.0]oct-1 (6), 2,4-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 13)

 (S)-2-(6-((2-chloro-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l(6),2,4-trien -2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

 2-(3S)-6-((2-chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0] octa-1, 3,5-Triene)benzyloxy)-2,3-dihydrobenzofuran-3-yl)acetate methyl ester 13E (340 mg, 0.58 mmol), suspended in methanol (5 mL) A solution of sodium hydroxide (480 mg, 12 mmol) in water (1 mL) was maintained at room temperature for 4 hours. Concentrate the reaction system to 1 mL, add water (10 mL), dilute hydrochloric acid with 2M to pH 3, extract with dichloromethane (20 mL x 2), combine organic phase, organic layer with water (10 mL x 2) Washing, drying with anhydrous sodium sulfate (2 g), EtOAc (EtOAc m. -(6-((2-chloro-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]oct-1(6),2,4-tri Alken-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid compound 13 (198 mg, 60%)

MS: 570.8 [M+l] ⁺ .

3⁄4 NMR (400 MHz, CDC1 ₃ ) 57.39 (m, 2H), 7.15 (dd, lH) 7.05 (d, lH), 6.59 (s, lH), 6.46 (m, 2H), 5.16 (s, 2H), 4.75(t,lH), 4.22(m,3H), 3.78(m,lH), 3.18(m,4H), 2.97(m,5H), 2.77(dd,lH), 2.57(dd,lH), 2.28 (m, 2H), 2.16 (s, 3H).

Example 14: (S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octyl -1,3,5-three blaze - ² - yl) benzyl) oxy) - ^2, 3-dihydro-benzofuran-3-yl) acetic acid (Compound I ⁴⁾

 (S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l,3,5-trien-2- Yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

 First step: 5-(5-Hydroxy-3-methylbicyclo[4.2.0]octyl-1,3,5-trien-2-yl)-2-methylbenzaldehyde (14B)

5-(5-hydroxy-3-methylbicyclo[4.2. methylbenzaldehyde

5-Bromo-4-methyl-bicyclo[4.2.0]oct-1,3,5-trien-2-ol 3e (600 mg, 2.82 mmol, intermediate 3) was dissolved in hydrazine, hydrazine-dimethyl In a mixed solution of carbamide (6 mL) and potassium carbonate (2M, 6 mL), (3-formyl-4-methylphenyl;) boronic acid 14A (555 mg, 3.38 mmol) and [Ι, Γ-bis(diphenylphosphino)ferrocene]palladium dichloride (103 mg, 0.141 mmol, Pd(dppf)Cl ₂ ), heated to 90 ° C and stirred for 3 hours, the system was suction filtered, and the filtrate was treated with ethyl acetate The ester (50 mL x 2) was extracted and the organic phase was washed with EtOAc (EtOAc) /v) = 10: 1) 5-(5-Hydroxy-3-methylbicyclo[4.2.0]oct-1,3,5-trien-2-yl)-2-methyl as a yellow solid Benzaldehyde 14B (374 mg, yield 58.0%).

 Step 2: 5-(3-(Hydroxymethyl)-4-methylphenyl)-4-methyl-cyclo[4.2.0]oct-1,3,5-trien-2-ol (14C )

5-(3-(hydroxymethyl)-4-methylphenyl)-4-methylbicyclo[4.2.0]octa-l,3,5-trien-2-ol

 Dissolve 5-(5-hydroxy-3-methylbicyclo[4.2.0]oct-1,3,5-trien-2-yl)-2-methylbenzaldehyde 14B (0.37 g, 1.47 mmol) In methanol (30 mL), sodium borohydride (277 mg, 7.3 mmol) was slowly added portionwise at 0 ° C, stirred at room temperature for 1 hour, and then quenched with water (50 mL). The solid was filtered with EtOAc (EtOAc) (EtOAc) (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH [4.2.0] Oct-1,3,5-trien-2-ol 14C crude product (320 mg, yield 85%).

 Third step: (2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]oct-1,3,5-triene- 2-yl)phenyl)methanol (14D)

 (2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l,3,5-trien-2-yl)phenyl )methanol

 5-(3-(Hydroxymethyl)-4-methylphenyl)-4-methylbicyclo[4.2.0]oct-1,3,5-trien-2-ol 14C (315 mg, 1.24 Methyl acetate was dissolved in hydrazine, hydrazine-dimethylformamide (25 mL), 3-methylsulfonylpropyl-4-methylbenzenesulfonic acid 1C (436 mg, 1.49 mmol) and cesium carbonate (513 mg, 1.73 mmol), heated to 80 ° C for 3 hours, filtered, and the filtrate was evaporated to dryness crystals crystals crystals 2-methyl-5-P-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]oct-1,3,5-trien-2-yl)phenyl ) methanol 14D (0.4 g, yield 86.0%)

 Fourth step: (S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octyl Methyl-1,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (14E)

 (S)-methyl2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octa-1,5 rien-2-yl)benzyl )oxy)-2,3-dihydrobenzofuran-3-yl)acetate

(2-Methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]oct-1,3,5-trien-2-yl Phenyl)methanol 14D (350 mg, 0.93 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 2d (214 mg, 1.03 mmol, intermediate 2) Dissolved in dichloromethane (10 mL), and under nitrogen, tributylphosphine (0.68 mL, 2.74 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (0.69 g, 2.74 mmol), stirred at room temperature for 3 hours, filtered, EtOAcjjjjjjjjjjjjjjjjj (S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octyl- 1 ,3 ,5-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid methyl ester 14E (430 mg, 82%).

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.30 (s, 1Η), 7.23 (d, 1H), 7.16 (dd, 1H), 7.03 (d, 1H), 6.60 (s, 1H), 6.52 - 6.46 (m , 2H), 5.02 (s, 2H), 4.75 (t, 1H), 4.29 - 4.21 (m, 3H), 3.81 (ddd, 1H), 3.72 (s, 3H) _: 3.29- 3.17 (m, 4H), 3.08― 3.01 (m, 2H), 2.96 (s, 3H), 2.75 (dd, 1H), 2.55 (dd, 1H), 2.38 (s, 3H), 2.31 (dt, 2H), 2.21 (s, 3H) .

 Step 5: (S)-2-(6-((2-Methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octyl -1,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 14)

 (S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0]octa-l,3,5-trien-2- Yl)benzyl)oxy)-2,3-dihy

 (S)-2-(6-((2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octane-1, Methyl 3,5-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate 14E (390 mg, 0.69 mmol) dissolved in methanol (5 mL) 2M sodium hydroxide solution (2 mL) was added to a mixed solution of tetrahydrofuran (5 mL), stirred at room temperature for 2 hours, concentrated under reduced pressure, water (25 mL) was added to the reaction mixture, and 1 M diluted hydrochloric acid was added dropwise. The mixture was extracted with ethyl acetate (25 mL×3). (v/v) =1 : 3) (S)-2-(6-; 2-methyl-5-(3-methyl-5-(3-(methylsulfonyl)) Propoxy)bicyclo[4.2.0]octyl-1,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid compound 14 (251 mg , yield 66%)

 MS: 549.0 [M-1] - .

3⁄4 NMR (400 MHz, CDC1 ₃ ) δ 7.30 (d, 1H), 7.23 (d, 1H), 7.17 (dd, 1H), 7.07 (d, 1H), 6.60 (s, 1H), 6.53 - 6.47 (m , 2H), 5.03 (s, 2H), 4.76 (t, 1H), 4.33 - 4.21 (m, 3H), 3.82 (ddd, 1H), 3.29 - 3.16 (m, 4H), 3.09- 3.01 (m, 2H ), 2.95 (s, 3H), 2.81 (dd, 1H), 2.62 (dd, 1H), 2.39 (s, 3H), 2.31 (ddd, 2H), 2.21 (s, 3H). Biological test cases

 1. GPR40 luciferase reporter gene test

 The activity of the compounds prepared in the various examples of the present invention was tested using the GPR40 luciferase reporter assay, and the test procedure was as follows:

The compound was formulated into a 10 mM stock solution in DMSO and diluted in 3 folds for use. The stable expression strain HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elkl was seeded at a suitable density in 96-well plates. The next day, waiting for the cells to meet The degree reached about 70%, replaced with serum-free medium, and starved overnight. On the third day, adding test compounds containing different concentrations

DMEM medium, 200 μl per well, was incubated in a cell culture incubator for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. The fluorescence data was fitted and analyzed using Origin 7 software, and the EC _{5Q of} each compound was calculated. The test results are shown in Table 1.

 Table 1 luciferase reporter gene test results

 Conclusion: The compound of the present invention exhibits superior pharmacodynamic activity as a GPR40 agonist as compared with the positive control. 2. Oral glucose tolerance test

 The hypoglycemic effect of the compounds prepared by the various examples of the present invention in sugar-loaded mice was evaluated by oral glucose tolerance test (OGTT). The test process is as follows:

 The animals used were SPF grade ICR mice, 18-22 g, female, purchased from Beijing Huakangkang Biotechnology Co., Ltd., Animal Production Certificate No.: SCXK (Beijing) 2009-0004. The purchased mice were induced with high fat diet for 25 days and fasted overnight. According to the basic blood glucose values after fasting, 10 groups in each group. The test compound was formulated into a 2 mg/ml suspension in 5% DMSO-15% solutol-80% physiological saline. The drug was administered by intragastric administration at a dose of 20 mg/kg. The blank control group was given 5% DMSO-15% solutol-80% saline. After 15 minutes of administration, 20% aqueous glucose solution (lg/kg) was administered, and the blood glucose level of each mouse was measured at 0, 15, 30, 45, 60, and 120 min using a Johnson & Johnson blood glucose meter. The area under the curve (AUC) is reduced by the ratio. The test results are shown in Table 2.

 Table 2 oral glucose tolerance test results

结论： 本发明化合物有较好的降糖效果。

Conclusion: The compounds of the present invention have a good hypoglycemic effect.

Claims

Claim A compound of the formula (I) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,

 among them: R is selected from hydrazine or d- ₈ fluorenyl; Ring A is selected from a 5- to 8-membered carbocyclic group or a 5- to 8-membered heterocyclic group, and said heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or 3 (=0) ₁₁ . The carbocyclic or heterocyclic group may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, nitro, cyano, d- ₈ fluorenyl, d- ₈ methoxy, C _{2 -8} alkenyl, C _{2 -8} alkynyl, -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C Substituting (=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ or -(CH ₂ ) _m -NR ⁷ R ^7a ; Ring B, including atoms attached to the benzene ring, together form a four-membered ring, and ring B may optionally be further from 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, nitro, cyano, d - ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R - (CH 2) m -C (= 0) -OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ or -(CH ₂ ) _m -NR ⁷ R ^7a substituent Substituting; R ¹ and R ⁴ are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- ₈ fluorenyl or d- ₈ decyloxy, said amino group, hydrazine group or a group optionally further substituted embankment 0-4 selected from F, Cl, Br, I, hydroxy, cyano, Ci_ ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, -(CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -( Substituent of CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a or -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a ; R ² and R ³ are each independently selected from H, F, Cl, Br, I, hydroxy, amino, cyano, carboxy, d- ₈ fluorenyl or d- ₈ decyloxy The amino, mercapto or decyloxy group is further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, cyano, Ci- ₈ fluorenyl, d- ₈ decyloxy, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m -C (= 0) -OR 7, -0-C (= 0) -OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a or -(CH ₂ ) _m -C(=0)-NR ⁷ Substituted by a substituent of R ^7a ; R ⁵ and R ⁶ are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, nitro, cyano, d- ₈ fluorenyl, d- ₈ decyloxy, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m -C (= 0) -OR 7, -0-C (= 0) -OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-R ⁷ , 3 to 10 membered carbocyclic group, 4 to 10 membered a cyclic group, a 3 to 10 membered carbocyclyloxy group or a 4 to 10 membered heterocyclic oxy group, said fluorenyl group, decyloxy group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, carbocyclic group The oxy or heterocyclic oxy group is optionally further selected from 0 to 4 F, Cl, Br, I, = 0, hydroxy, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, - (CH _{2) m} - C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-NR ⁷ R ^7a , -N(R ^7b )- Substituted by a substituent of C(=0)-R ⁷ , a 3 to 10 membered carbocyclic group, a 4 to 10 membered heterocyclic group, a 3 to 10 membered carbocyclyloxy group or a 4 to 10 membered heterocyclic oxy group, And the heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or 3 (=0) ₁₁ ; Alternatively, R ⁵ and R ⁶ may form a 4 to 8 membered carbocyclic ring or a 5 to 8 membered heterocyclic ring, and the carbocyclic or heterocyclic ring may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, and I. , = 0, hydroxy, nitro, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0 )-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ or Substituted by a substituent of -(CH ₂ ) _m -NR ⁷ R ^7a , and the heterocyclic ring contains 1 to 4 atoms or groups selected from N, 0 or S(=0) _n ; Y is selected from the group consisting of a single bond, -0-, -NR ⁷ -, -S(=0) _n -, -C(=0)-, -d_ ₈ fluorenylene or -O-Cu fluorenylene, said The fluorenylene group is optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , cyano, hydroxy, d- ₈ fluorenyl, Ci- ₈ fluorenyloxy , C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m -C (= 0) -0-R 7, - (CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -0-C(=0)-0-R ⁷ or -NR Substituted by a substituent of ⁷ R ^7a ; X is selected from H, F, Cl, Br, I, hydroxy, nitro, cyano, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl, - ( CH ₂ ) _m -C(=0)-R ⁷ , -(CH ₂ ) _m -C(=0)-OR ⁷ , -0-C(=0)-OR ⁷ , -(CH ₂ ) _m -S (=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0 -NR ⁷ R ^7a , -N(R ^7b )-C(=0)-R ⁷ , -(CH ₂ ) _n -3 to 10 membered carbocyclic group, -(CH ₂ ) _n -4 to 10 membered a cyclic group, -(CH ₂ ) _n -0-3 to 10 membered carbocyclic group or 4 to 10 membered heterocyclic oxy group, said fluorenyl group, decyloxy group, alkenyl group, alkynyl group, carbocyclic group, The heterocyclic or heterocyclic oxy group is further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, =0, hydroxy, nitro, cyano, d- ₈ fluorenyl, d- ₈ fluorenyloxy , C ₂ - ₈ alkenyl, C ₂ - _{8 alkynyl, - (CH 2) m -C} (= 0) -R 7, - (CH 2) m -C (= 0) -OR 7, -0- C(=0)-OR ⁷ , -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _m -NR ⁷ R ^7a , -(CH ₂ ) _m -C(=0) -NR ⁷ R ^7a , -N(R ^7b )-C(=0)-NR ⁷ R ^7a , -N(R ^7b )-C(=0)-R ⁷ , 3 to 10 membered carbocyclic group, 4 to 10 membered heterocyclic group, 3 to 10 A substituted carbocyclyl group or a 4-10 yuan heterocyclic oxy group substituted with the group, and the heterocyclic group containing 1 to 4 heteroatoms selected from N, 0 or 3 (= 0;) atom or a group of ₁₁ group; R ^7, 1 and R ^7b are each independently selected from H, hydroxy, amino, carboxy, d- ₈ alkyl with, d- ₈ embankment group, C ₂ - ₈ alkenyl, C _{2 .8} alkynyl, 3 to 10 membered carbocyclic group, 4 to 10 membered heterocyclic group, 3 to 10 membered carbocyclyloxy group or 4 to 10 membered heterocyclic oxy group, said amino group, fluorenyl group , methoxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further selected from 0 to 4 selected from F, Cl, Br, I, =0 , hydroxy, amino, nitro, cyano, carboxy, d- ₈ alkyl with, d_ ₈ embankment group, C ₂ - ₈ alkenyl, C ₂ - ₈ alkynyl group, 3-10 yuan carbocyclyl, 4-10 Substituted by a heterocyclic group, a 3- to 10-membered carbocyclyloxy group or a 4- to 10-membered heterocyclic oxy group, and the heterocyclic group contains 1 to 4 selected from N, 0 or S ( =0) an atom or group of _n ; p is selected from 0, 1, 2 or 3; q is selected from 0, 1, 2, 3 or 4;  t is selected from 0, 1 or 2;  m is selected from 0, 1, 2, 3, 4 or 5;  n is selected from 0, 1 or 2.  2. A compound according to claim 1 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of II) Compounds shown:

 among them- RH or d- ₄

 Ring B, comprising atoms connected to the benzene ring to form a four-membered ring; R ¹ and R ⁴ are each independently selected from F, Cl, Br or d ₄ fluorenyl; R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br or d ₄ fluorenyl; Y is selected from a single bond, -0- or -Od- ₄ , and the fluorenylene group is further optionally 0 to 4 selected from -(CH ₂ ) _m -S(=0) _n -R ⁷ Substituted by a substituent; X is selected from H, d ₄ fluorenyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To an 8-membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, the fluorenyl, carbocyclic or heterocyclic group optionally further selected from 0 to 4 selected from a hydroxyl group or d a substituent substituted with ₄ methoxy groups, and the heterocyclic group contains 1 to 4 atoms or groups selected from N, 0 or S(=0) _n ; R ^{7 is} selected from H or d ₄ thiol;  p is selected from 0, 1 or 2;  q is selected from 0, 1 or 2;  m is selected from 0, 1, 2, 3, 4 or 5;  n is selected from 0, 1 or 2. 3. The compound according to claim 2 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of Compounds shown in III):

 among them:  Ring B, comprising atoms connected to the benzene ring to form a four-membered ring; R ⁵ and R ⁶ are each independently selected from H, F, Cl, Br or d ₄ fluorenyl;  Y is selected from -Ο- or -O-CM fluorene; X is selected from H, d ₄ fluorenyl, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -3 to 8 membered carbocyclic group, -(CH ₂ ) _n -4 To an 8-membered heterocyclic group or a -(CH ₂ ) _n -0-3 to 8 membered carbocyclic group, the fluorenyl, carbocyclic or heterocyclic group optionally further selected from 0 to 4 selected from hydroxy or CM Substituted by a substituent of a methoxy group; R ^{7 is} selected from H or d- ₄ fluorenyl;  m is selected from 0, 1, 2, 3 or 4;  n is selected from 0, 1 or 2.  The compound according to claim 3 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt thereof, eutectic, wherein the compound is selected from the group consisting of the formula (IV) Compound shown:

 among them- R ^{5 is} selected from H or d- ₄ fluorenyl; R ⁶ is H; X is selected from H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -4 to 6-membered carbocyclic group, -(CH ₂ ) _n -5 to 8 membered heterocyclic ring Base or a -(CH ₂ ) _n -0-3 to 5-membered carbocyclic group, which is optionally further substituted with 0 to 2 substituents selected from a hydroxyl group or a d- ₄ alkoxy group ; R ^{7 is} selected from the group consisting of d- ₄ fluorenyl;  m is selected from 2, 3 or 4;  n is selected from 0, 1 or 2.  5. A compound according to claim 4 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein: R ^{5 is} selected from H, methyl, ethyl, n-propyl or isopropyl; R ⁶ is H; X selects H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ ,

R ^{7 is} selected from methyl, ethyl, n-propyl or isopropyl.  6. A compound according to claim 5 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein: R ^{5 is} selected from H, methyl or ethyl; R ⁶ is H; X is selected from H, -(CH ₂ ) ₃ -S(=0) ₂ -R ⁷ ,

; R ⁷ is a methyl group.  The compound according to claim 2 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected from the formula ( Compound shown by V):

 among them: R ^{4 is} selected from H, F, CI or methyl; R ^{5 is} selected from H or d- ₄ fluorenyl; X is selected from H, -(CH ₂ ) _m -S(=0) _n -R ⁷ , -(CH ₂ ) _n -4 to 6-membered carbocyclic group, -(CH ₂ ) _n -5 to 8 membered heterocyclic ring Or a -(CH ₂ ) _n -0-3 to 5-membered carbocyclic group, the carbocyclic or heterocyclic group optionally further having 0 to 2 substituents selected from a hydroxyl group or a d- ₄ alkoxy group Replaced R ^{7 is} selected from H or d- ₄ fluorenyl;  m is selected from 0, 1, 2, 3 or 4; n is selected from 0, 1 or 2. 8. A compound according to claim 7 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein: R ^{4 is} selected from H, F, CI or methyl; R ⁵ is H or methyl; X is selected from H, -(CH ₂ ) ₃ -S(=0) ₂ -CH ₃ ,

or Oh.  9. The compound according to claim 1 or a stereoisomer, hydrate, ester, metabolite, solvate thereof,

10. A compound according to claim 9 or a stereoisomer, hydrate, ester, metabolite, solvate thereof,

 The compound according to any one of claims 1 to 10, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the pharmacy thereof The salt described in the above acceptable salt is selected from the group consisting of sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethylammonium salt, two Ethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt, methylpyridine salt, 2,6-di Methylpyridine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine salt, N-ethyl piperidine salt, polyamine resin salt , phenicillin salt or a combination thereof.  The compound according to claim 11 or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the salt is selected from the group consisting of sodium salt a potassium salt, an ammonium salt, a triethylamine salt, an ethanolamine salt, a diethanolamine salt or a combination thereof.  13. A process for the preparation of a compound according to any one of claims 1 to 10 which may be selected from process 1 or process 2 comprising the following steps: method one:

 General formula (I-aO compound by Clemson reduction, improved Clemson reduction, Wolf-Kessina reduction, Huangminglong reduction or reducing agent-Lewis acid group I-a); B person R ⁹

(lc) The compound of the formula (Ia) is subjected to a suzuki coupling reaction with the compound of the formula (Ib), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (Ic);

(l-ai) (la ₂ ) a compound of the formula (Ia ₂ ) obtained by reducing a carbonyl group by a reducing agent to obtain a compound of the formula (Ia ₂ ); or a formula (I-aO for reducing a carbonyl group to a hydroxyl group by a reducing agent and then undergoing a nucleophilic substitution reaction to obtain a formula ( 1-) compound;

The compound of the formula (Ia ₂ ) is reduced to give a compound of the formula (Ia); or the compound of the formula (1) is reduced to give a compound of the formula (Ia);

 (l-a) (l-c)  The compound of the formula (I-a) is subjected to a suzuki coupling reaction with the compound of the formula (I-b), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (I-c);

a product obtained by reacting a compound of the formula (Id) with a compound of the formula (Ie) by Mistimobu, and further hydrolyzed to obtain a compound of the formula (I); 0, wherein R ⁹ or R ¹² are each independently selected from H, F, Cl , Br, I, hydroxyl, ^^,

O' , R ^{1Q is} selected from H, F, Cl, Br, I, hydroxy, d ₆ fluorenyl or d ₆ methoxy, X, Y, ring B, R, R ¹ , R ² , R ³ , R ⁴ The definitions of R ⁵ , R ⁶ , p, q and t are identical to those defined in any of claims 1-10.  A pharmaceutical composition, comprising: an effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, hydrate, ester, metabolite, solvate thereof, a pharmaceutically acceptable salt, eutectic or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient;  The composition may further comprise one or more additional therapeutic agents.  15. The pharmaceutical composition of claim 14, wherein the additional therapeutic agent comprises: (a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or  (c) an SGLT-2 inhibitor or a pharmaceutically acceptable salt, and/or (d) a PPAR _T agonist or a _{γ γ} partial agonist or a pharmaceutically acceptable salt, and/or  (e) a PPAR^ dual agonist or pharmaceutically acceptable salt, and/or (f) a PPAR _s agonist or pharmaceutically acceptable salt, and/or  (g) insulin or pseudo-insulin or a pharmaceutically acceptable salt, and / or  (h) a protein tyrosine phosphatase-ΙΒ(ΡΤΡ-ΙΒ) inhibitor or a pharmaceutically acceptable salt, and/or  (i) a sulfonylurea inhibitor or a pharmaceutically acceptable salt, and/or  (D a-glucosidase inhibitor or pharmaceutically acceptable salt, and/or  (k) a GLP-K GLP-1 analog, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or  (1) a glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or  (m) anti-inflammatory drugs, and / or  (n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or  (0) diet pills, and / or  (p) A drug for improving lipid distribution in a patient selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, niacin or a salt thereof, ? Enter! An agonist, a cholesterol absorption inhibitor, an acyl-CoA (cholesterol acyltransferase (ACAT)) inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or  (q) biguanides, thiazolidinediones, linoleides or pharmaceutically acceptable salts or prodrugs thereof.  16. The pharmaceutical composition according to claim 15, wherein the GPR40 agonist is selected from the group consisting of fasigli & m hemihydrates (TAK-875) or a pharmaceutically acceptable salt or prodrug thereof. The pharmaceutical composition according to claim 15, wherein the DDPIV inhibitor is selected from the group consisting of linagliptini; linagliptin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vidaliptin) ), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin (carbagliptin), Melogliptin (Merolidine), Dutogliptin (Digliptin), Teneligliptin ( Territoryin, Gemigliptin or Trelagliptin; SGLT-2 inhibitor is selected from the group consisting of Dapagliflozin, Canagliflozin, Atigliflozin List), Empagliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin ) or Ertugliflozin (net relies column); PPAR _Y agonists include ciglitazone (ciglitazone), troglitazone (troglitazone), pioglitazone (pioglitazone), rosiglitazone (rosiglitazone) Englitazone (englitazone), DarglitazoanC darglitazone), the PPAR ^ dual agonists include muraglitazar (muraglitazar) or aleglitazar (Aleglitazar), comprising the PPAR _S agonist of pioglitazone (pioglitazone) Or rosiglitazone (roglitazone). The pharmaceutical composition according to claim 15, wherein the biguanide therapeutic agent is selected from metformin or diethylbiguanide; and the thiazolidinedione therapeutic agent is selected from the group consisting of Ciglitazone (cycloglitazone) and Pioglitazone (pioglitazone) ), Rosiglitazone, Roglitazone, Farglitazar or Darglitazonan; the sulfonylurea inhibitor is selected from the group consisting of Glimepiride ), Tolglybutamide, Glibornuride, Glibenclamide, Gliquidone, Glipizide or Gliclazipe; glibenclamide The agent is selected from the group consisting of Nateglinide, Repaglinide, or Mitiglinide; the α-glucosidase inhibitor is selected from the group consisting of Acarbose (Acarbose) and Miglitol (; Voglibose) or miglitol; the GLP-1 or GLP-1 analogue is selected from Exenatide or Liraglutide.  19. The compound of any one of claims 1 to 12, or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, or claim 14 - Use of the pharmaceutical composition according to any one of 18 in the preparation of a G protein coupled receptor 40 agonist, in particular as a G protein coupled receptor 40 agonist, preferably for use in the preparation of a pharmaceutical preparation Use in pharmaceutical preparations for the treatment and/or prevention of metabolic diseases.  20. The use according to claim 19, wherein the metabolic diseases include diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, high insulin Hyperemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease , ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, arterial atherosclerosis One or more of sclerosing, sequelae, limp, heart attack or stroke.  21. The use according to claim 20, wherein the metabolic disease comprises type II diabetes.  A method for the treatment and/or prevention of a metabolic disease, which comprises administering to a subject an effective amount of a compound according to any one of claims 1 to 12, or a stereoisomer, hydrate, ester or solvent thereof. A compound, a co-crystal, a metabolite, a pharmaceutically acceptable salt or prodrug or a pharmaceutical composition according to any one of claims 14-18.  23. The method according to claim 22, wherein the metabolic diseases include diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, high Insulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney Disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, arteries A atherosclerosis and its sequelae one or more of angina, limp, heart attack or stroke.